ORCID Profile
0000-0003-4423-934X
Current Organisation
University of Sydney
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Research Topics
In Research Link Australia (RLA), "Research Topics" refer to ANZSRC FOR and SEO codes. These topics are either sourced from ANZSRC FOR and SEO codes listed in researchers' related grants or generated by a large language model (LLM) based on their publications.
Top 5 Research Topics
ANZSRC Field of Research (FoR)
Genetics | Developmental Genetics (incl. Sex Determination) | Epigenetics (incl. Genome Methylation and Epigenomics) | Genetic Immunology | Genome Structure and Regulation | Genomics | Biochemistry and Cell Biology | Regenerative Medicine (incl. Stem Cells and Tissue Engineering) | Bioinformatics | Biological Adaptation
ANZSRC Socio-Economic Objective (SEO)
Expanding Knowledge in the Biological Sciences | Inherited Diseases (incl. Gene Therapy) | Expanding Knowledge in Technology |
Related Links
Publications
Genome-wide analysis of long noncoding RNA stability.
Publisher: Cold Spring Harbor Laboratory
Date: 09-03-2012
Abstract: Transcriptomic analyses have identified tens of thousands of intergenic, intronic, and cis -antisense long noncoding RNAs (lncRNAs) that are expressed from mammalian genomes. Despite progress in functional characterization, little is known about the post-transcriptional regulation of lncRNAs and their half-lives. Although many are easily detectable by a variety of techniques, it has been assumed that lncRNAs are generally unstable, but this has not been examined genome-wide. Utilizing a custom noncoding RNA array, we determined the half-lives of ∼800 lncRNAs and ∼12,000 mRNAs in the mouse Neuro-2a cell line. We find only a minority of lncRNAs are unstable. LncRNA half-lives vary over a wide range, comparable to, although on average less than, that of mRNAs, suggestive of complex metabolism and widespread functionality. Combining half-lives with comprehensive lncRNA annotations identified hundreds of unstable (half-life 2 h) intergenic, cis -antisense, and intronic lncRNAs, as well as lncRNAs showing extreme stability (half-life 16 h). Analysis of lncRNA features revealed that intergenic and cis -antisense RNAs are more stable than those derived from introns, as are spliced lncRNAs compared to unspliced (single exon) transcripts. Subcellular localization of lncRNAs indicated widespread trafficking to different cellular locations, with nuclear-localized lncRNAs more likely to be unstable. Surprisingly, one of the least stable lncRNAs is the well-characterized paraspeckle RNA Neat1 , suggesting Neat1 instability contributes to the dynamic nature of this subnuclear domain. We have created an online interactive resource ( stability.matticklab.com ) that allows easy navigation of lncRNA and mRNA stability profiles and provides a comprehensive annotation of ∼7200 mouse lncRNAs.
Targeted RNA sequencing reveals the deep complexity of the human transcriptome
Publisher: Springer Science and Business Media LLC
Date: 13-11-2012
DOI: 10.1038/NBT.2024
Claudin-11 and occludin are major contributors to Sertoli cell tight junction function, in vitro
Publisher: Medknow
Date: 2016
The extent of functionality in the human genome
Publisher: Springer Science and Business Media LLC
Date: 15-07-2013
Exploring the Role of Non-Coding RNAs in the Pathophysiology of Systemic Lupus Erythematosus
Publisher: MDPI AG
Date: 22-06-2020
DOI: 10.3390/BIOM10060937
Abstract: Systemic lupus erythematosus (SLE) is a chronic immune-related disorder designated by a lack of tolerance to self-antigens and the over-secretion of autoantibodies against several cellular compartments. Although the exact pathophysiology of SLE has not been clarified yet, this disorder has a strong genetic component based on the results of familial aggregation and twin studies. Variation in the expression of non-coding RNAs has been shown to influence both susceptibility to SLE and the clinical course of this disorder. Several long non-coding RNAs (lncRNAs) such as GAS5, MALAT1 and NEAT1 are dysregulated in SLE patients. Moreover, genetic variants within lncRNAs such as SLEAR and linc00513 have been associated with risk of this disorder. The dysregulation of a number of lncRNAs in the peripheral blood of SLE patients has potentiated them as biomarkers for diagnosis, disease activity and therapeutic response. MicroRNAs (miRNAs) have also been shown to affect apoptosis and the function of immune cells. Taken together, there is a compelling rationale for the better understanding of the involvement of these two classes of non-coding RNAs in the pathogenesis of SLE. Clarification of the function of these transcripts has the potential to elucidate the molecular pathophysiology of SLE and provide new opportunities for the development of targeted therapies for this disorder.
Defining the genetic basis of early onset hereditary spastic paraplegia using whole genome sequencing
Publisher: Springer Science and Business Media LLC
Date: 28-09-2016
Non-coding RNAs: Regulators of disease
Publisher: Wiley
Date: 30-10-2010
DOI: 10.1002/PATH.2638
Abstract: For 50 years the term 'gene' has been synonymous with regions of the genome encoding mRNAs that are translated into protein. However, recent genome-wide studies have shown that the human genome is pervasively transcribed and produces many thousands of regulatory non-protein-coding RNAs (ncRNAs), including microRNAs, small interfering RNAs, PIWI-interacting RNAs and various classes of long ncRNAs. It is now clear that these RNAs fulfil critical roles as transcriptional and post-transcriptional regulators and as guides of chromatin-modifying complexes. Here we review the biology of ncRNAs, focusing on the fundamental mechanisms by which ncRNAs facilitate normal development and physiology and, when dysfunctional, underpin disease. We also discuss evidence that intergenic regions associated with complex diseases express ncRNAs, as well as the potential use of ncRNAs as diagnostic markers and therapeutic targets. Taken together, these observations emphasize the need to move beyond the confines of protein-coding genes and highlight the fact that continued investigation of ncRNA biogenesis and function will be necessary for a comprehensive understanding of human disease.
Environmental and genetic disease modifiers of haploinsufficiency of A20
Publisher: Cold Spring Harbor Laboratory
Date: 20-03-2022
DOI: 10.1101/2022.03.19.485004
Abstract: Monogenic diseases can often manifest erse clinical phenotypes and cause diagnostic dilemmas. While monoallelic loss-of-function variants in TNFAIP3 (Haploinsufficiency of A20 HA20) cause a highly penetrant autoinflammatory disease, the variable expressivity suggest a role for additional genetic and environmental disease modifiers. Here, we identify critically ill children who inherited a family-specific TNFAIP3 deletion from one of their otherwise healthy parents. Each of the probands also inherited in trans a subtle loss-of-function I207L TNFAIP3 variant that is common in Oceania, originally introgressed from Denisovans. Modelling this compound heterozgous state in mice under specific pathogen free conditions demonstrated a reduced threshold to break immune tolerance. Exaggerated immune responses were precipitated by inheriting the two genetic hits on the TNFAIP3 checkpoint coupled with increasing the microbial challenge to immune tolerance, either by co-housing with pet store mice carrying a wild microbial burden or by transient dietary exposure to a chemical that diminishes the intestinal mucin barrier separating gut microbes from immune sensing systems. These data illuminate second-hit genetic and environmental modifiers contributing to complex inflammatory and autoimmune disease. Increased mechanistic understanding of the presence and contribution of disease modifiers will aid diagnostic and prognostic patient stratification and potentially reveal novel therapeutic opportunities.
The BET bromodomain inhibitor exerts the most potent synergistic anticancer effects with quinone-containing compounds and anti-microtubule drugs
Publisher: Impact Journals, LLC
Date: 13-10-2016
A review of the development of tumor vasculature and its effects on the tumor microenvironment
Publisher: Informa UK Limited
Date: 04-2017
DOI: 10.2147/HP.S133231
Evolutionary conservation of embryonic DNA methylome remodelling in distantly related teleost species
Publisher: Cold Spring Harbor Laboratory
Date: 24-05-2023
DOI: 10.1101/2023.05.24.542066
Abstract: Methylation of cytosines in the CG context (mCG) is the most abundant DNA modification in vertebrates that plays crucial roles in cellular differentiation and identity. After fertilization, DNA methylation patterns inherited from parental gametes are remodelled into a state compatible with embryogenesis. In mammals, this is achieved through the global erasure and re-establishment of DNA methylation patterns. However, in non-mammalian vertebrates like zebrafish, no global erasure has been observed. To investigate the evolutionary conservation and ergence of DNA methylation remodelling in teleosts, we generated base resolution DNA methylome datasets of developing medaka and medaka-zebrafish hybrid embryos. In contrast to previous reports, we show that medaka display comparable DNA methylome dynamics to zebrafish with high gametic mCG levels (sperm: ∼90% egg: ∼75%), and adoption of a paternal-like methylome during early embryogenesis, with no signs of prior DNA methylation erasure. We also demonstrate that non-canonical DNA methylation (mCH) reprogramming at TGCT tandem repeats is a conserved feature of teleost embryogenesis. Lastly, we find remarkable evolutionary conservation of DNA methylation remodelling patterns in medaka-zebrafish hybrids, indicative of compatible DNA methylation maintenance machinery in far-related teleost species. Overall, these results suggest strong evolutionary conservation of DNA methylation remodelling pathways in teleosts, which is distinct from the global DNA methylome erasure and reestablishment observed in mammals.
The melanoma-upregulated long noncoding RNA SPRY4-IT1 modulates apoptosis and invasion.
Publisher: American Association for Cancer Research (AACR)
Date: 31-05-2011
DOI: 10.1158/0008-5472.CAN-10-4460
Abstract: The identification of cancer-associated long noncoding RNAs (lncRNAs) and the investigation of their molecular and biological functions are important to understand the molecular biology of cancer and its progression. Although the functions of lncRNAs and the mechanisms regulating their expression are largely unknown, recent studies are beginning to unravel their importance in human health and disease. Here, we report that a number of lncRNAs are differentially expressed in melanoma cell lines in comparison to melanocytes and keratinocyte controls. One of these lncRNAs, SPRY4-IT1 (GenBank accession ID AK024556), is derived from an intron of the SPRY4 gene and is predicted to contain several long hairpins in its secondary structure. RNA-FISH analysis showed that SPRY4-IT1 is predominantly localized in the cytoplasm of melanoma cells, and SPRY4-IT1 RNAi knockdown results in defects in cell growth, differentiation, and higher rates of apoptosis in melanoma cell lines. Differential expression of both SPRY4 and SPRY4-IT1 was also detected in vivo, in 30 distinct patient s les, classified as primary in situ, regional metastatic, distant metastatic, and nodal metastatic melanoma. The elevated expression of SPRY4-IT1 in melanoma cells compared to melanocytes, its accumulation in cell cytoplasm, and effects on cell dynamics, including increased rate of wound closure on SPRY4-IT1 overexpression, suggest that the higher expression of SPRY4-IT1 may have an important role in the molecular etiology of human melanoma. Cancer Res 71(11) 3852–62. ©2011 AACR.
Supplemental Files from Lipid Uptake Is an Androgen-Enhanced Lipid Supply Pathway Associated with Prostate Cancer Disease Progression and Bone Metastasis
Publisher: American Association for Cancer Research (AACR)
Date: 03-04-2023
DOI: 10.1158/1541-7786.22513437
Abstract: Figure S1: LNCaP, VCaP and DuCaP cells were grown in charcoal-dextran stripped serum (CSS) for 48 h and treated with increasing concentrations of R1881 or DHT in the presence or absence of Enzalutamide (10 µM) or vehicle (Ctrl) for 48 h. Figure S2: Androgens increased lipid uptake of long-chain fatty acids. LAPC4 cells were grown in CSS for 48 h and treated with 1 nM R1881 or vehicle for 48 h. Figure S3: (A) LNCaP cells were synchronized in G0/G1 by androgen deprivation (CSS for 48 h) followed by treatment with Tunicamycin (1 mg/mL), Hydroxyurea (1 M), or Nocodazole (25 ug/mL) for another 24 h, placing cell cycle blocks in G0/G1, S phase and mitosis, respectively. Figure S4: Oncomine analysis of candidate lipid transporters in (A) Grasso [2], (B) Varambally [3] and (C) LaTulippe datasets [4] comparing gene expression of normal prostate gland versus localized, primary prostate cancer tumor s les. Figure S5: (A) DuCaP (top panel) and VCaP cells (bottom panel) were grown in CSS for 48 h and treated with 10 nM DHT in the absence or presence of Enz (10 µM) or vehicle (Ctrl) for 48 h. Table S1. Primer sequences
Germline variants in familial pituitary tumour syndrome genes are common in young patients and families with additional endocrine tumours
Publisher: Oxford University Press (OUP)
Date: 05-2017
DOI: 10.1530/EJE-16-0944
Abstract: Familial pituitary tumour syndromes (FPTS) account for 5% of pituitary adenomas. Multi-gene analysis via next-generation sequencing (NGS) may unveil greater prevalence and inform clinical care. We aimed to identify germline variants in selected patients with pituitary adenomas using a targeted NGS panel. We undertook a nationwide cross-sectional study of patients with pituitary adenomas with onset ≤40 years of age and/or other personal/family history of endocrine neoplasia. A custom NGS panel was performed on germline DNA to interrogate eight FPTS genes. Genome data were analysed via a custom bioinformatic pipeline, and validation was performed by Sanger sequencing. Multiplex ligation-dependent probe lification (MLPA) was performed in cases with heightened suspicion for MEN1 , CDKN1B and AIP mutations. The main outcomes were frequency and pathogenicity of rare variants in AIP , CDKN1B , MEN1 , PRKAR1A , SDHA , SDHB , SDHC and SDHD . Forty-four patients with pituitary tumours, 14 of whom had a personal history of other endocrine tumours and/or a family history of pituitary or other endocrine tumours, were referred from endocrine tertiary-referral centres across Australia. Eleven patients (25%) had a rare variant across the eight FPTS genes tested: AIP (p.A299V, p.R106C, p.F269F, p.R304X, p.K156K, p.R271W), MEN1 (p.R176Q), SDHB (p.A2V, p.S8S), SDHC (p.E110Q) and SDHD (p.G12S), with two patients harbouring dual variants. Variants were classified as pathogenic or of uncertain significance in 9/44 patients (20%). No deletions/duplications were identified in MEN1 , CDKN1B or AIP . A high yield of rare variants in genes implicated in FPTS can be found in selected patients using an NGS panel. It may also identify in iduals harbouring more than one rare variant.
Genomic diagnostics in polycystic kidney disease: an assessment of real-world use of whole-genome sequencing
Publisher: Springer Science and Business Media LLC
Date: 12-01-2021
Growth phase‐dependent expression and degradation of histones in the thermophilic archaeon Thermococcus zilligii
Publisher: Wiley
Date: 05-2000
DOI: 10.1046/J.1365-2958.2000.01904.X
Abstract: HTz is a member of the archaeal histone family. The archaeal histones have primary sequences and structural similarity to the eukaryal histone fold domain, and are thought to resemble the archetypal ancestor of the eukaryal nucleosome core histones. The effects of growth phase on the total soluble proteins from Thermococcus zilligii, isolated after various stages of growth from mid-logarithmic to late stationary phase, were examined by denaturing polyacrylamide gel electrophoresis. On entry into stationary phase, at least 11 proteins were detected that changed considerably in level. One of these proteins was identified by Western hybridization as HTz. The level of HTz decreased dramatically as cells entered stationary phase, and it could not be detected by late stationary phase. Unexpectedly, the Western hybridization detected a second protein, with an estimated molecular mass of approximately 14 kDa, which paralleled the decrease in level of HTz. Native purified HTz was shown to retain complete activity after prolonged incubation at the growth temperature of the organism, suggesting that the decrease in HTz was a specific cell-regulated process. Analysis of native purified HTz by electrospray ionization mass spectrometry revealed the molecular masses of HTz1 and HTz2 to be 7204 +/- 3 Da and 7016 +/- 3 Da respectively. The only non-covalent species that was detected corresponded to the molecular mass of an HTz1-HTz2 heterodimer. Northern analyses of T. zilligii total RNA with an htz1 gene probe indicated a rapid decrease in expression of htz1 with progression of the growth phase, and complete repression of htz1 transcript synthesis by late logarithmic phase. Three proteins that changed in level with growth phase were identified by N-terminal sequence analysis. The first was homologous to a hypothetical protein conserved in all Archaea sequenced to date, the second to the Sac10b family of archaeal DNA-binding proteins and the third to the C-terminal region of the leucine-responsive regulatory family of DNA-binding proteins (LRPs).
Mutation allele burden remains unchanged in chronic myelomonocytic leukaemia responding to hypomethylating agents
Publisher: Springer Science and Business Media LLC
Date: 24-02-2016
DOI: 10.1038/NCOMMS10767
Abstract: The cytidine analogues azacytidine and 5-aza-2’-deoxycytidine (decitabine) are commonly used to treat myelodysplastic syndromes, with or without a myeloproliferative component. It remains unclear whether the response to these hypomethylating agents results from a cytotoxic or an epigenetic effect. In this study, we address this question in chronic myelomonocytic leukaemia. We describe a comprehensive analysis of the mutational landscape of these tumours, combining whole-exome and whole-genome sequencing. We identify an average of 14±5 somatic mutations in coding sequences of sorted monocyte DNA and the signatures of three mutational processes. Serial sequencing demonstrates that the response to hypomethylating agents is associated with changes in DNA methylation and gene expression, without any decrease in the mutation allele burden, nor prevention of new genetic alteration occurence. Our findings indicate that cytosine analogues restore a balanced haematopoiesis without decreasing the size of the mutated clone, arguing for a predominantly epigenetic effect.
IL-21 contributes to fatal inflammatory disease in the absence of Foxp3+ T regulatory cells.
Publisher: The American Association of Immunologists
Date: 15-02-2014
Abstract: The cytokine IL-21 has been shown to influence immune responses through both costimulatory effects on effector T cells and opposing inhibitory effects on T regulatory cells (Tregs). To distinguish the effect of IL-21 on the immune system from that of its effect on Tregs, we analyzed the role of IL-21/IL-21R signaling in mice made genetically deficient in IL-2, which exhibit a deficit in IL-2–dependent Foxp3 regulatory T cells and suffer from a fatal multiorgan inflammatory disease. Our findings demonstrate that in the absence of IL-21/IL-21R signaling, Il2−/− mice retained a deficiency in Tregs yet exhibited a reduced and delayed inflammatory disease. The improved health of Il2−/−Il21r−/− mice was reflected in reduced pancreatitis and hemolytic anemia and this was associated with distinct changes in lymphocyte effector populations, including the reduced expansion of both T follicular helper cells and Th17 cells and a compensatory increase in IL-22 in the absence of IL-21R. IL-21/IL-21R interactions were also important for the expansion of effector and memory CD8+ T cells, which were critical for the development of pancreatitis in Il2−/− mice. These findings demonstrate that IL-21 is a major target of immune system regulation.
Identification of a novel fusion transcript between human relaxin-1 (RLN1) and human relaxin-2 (RLN2) in prostate cancer
Publisher: Elsevier BV
Date: 2016
DOI: 10.1016/J.MCE.2015.10.011
Abstract: Simultaneous expression of highly homologous RLN1 and RLN2 genes in prostate impairs their accurate delineation. We used PacBio SMRT sequencing and RNA-Seq in LNCaP cells in order to dissect the expression of RLN1 and RLN2 variants. We identified a novel fusion transcript comprising the RLN1 and RLN2 genes and found evidence of its expression in the normal and prostate cancer tissues. The RLN1-RLN2 fusion putatively encodes RLN2 isoform with the deleted secretory signal peptide. The identification of the fusion transcript provided information to determine unique RLN1-RLN2 fusion and RLN1 regions. The RLN1-RLN2 fusion was co-expressed with RLN1 in LNCaP cells, but the two gene products were inversely regulated by androgens. We showed that RLN1 is underrepresented in common PCa cell lines in comparison to normal and PCa tissue. The current study brings a highly relevant update to the relaxin field, and will encourage further studies of RLN1 and RLN2 in PCa and broader.
Endogenous microRNA sponges: evidence and controversy.
Publisher: Springer Science and Business Media LLC
Date: 04-04-2016
DOI: 10.1038/NRG.2016.20
Abstract: The competitive endogenous RNA (ceRNA) hypothesis proposes that transcripts with shared microRNA (miRNA) binding sites compete for post-transcriptional control. This hypothesis has gained substantial attention as a unifying function for long non-coding RNAs, pseudogene transcripts and circular RNAs, as well as an alternative function for messenger RNAs. Empirical evidence supporting the hypothesis is accumulating but not without attracting scepticism. Recent studies that model transcriptome-wide binding-site abundance suggest that physiological changes in expression of most in idual transcripts will not compromise miRNA activity. In this Review, we critically evaluate the evidence for and against the ceRNA hypothesis to assess the impact of endogenous miRNA-sponge interactions.
A Pathway to Precision Medicine for Aboriginal Australians: A Study Protocol
Publisher: MDPI AG
Date: 21-06-2021
DOI: 10.3390/MPS4020042
Abstract: (1) Background: Genomic precision medicine (PM) utilises people’s genomic data to inform the delivery of preventive and therapeutic health care. PM has not been well-established for use with people of Aboriginal and Torres Strait Islander ancestry due to the paucity of genomic data from these communities. We report the development of a new protocol using co-design methods to enhance the potential use of PM for Aboriginal Australians. (2) Methods: This iterative qualitative study consists of five main phases. Phase-I will ensure appropriate governance of the project and establishment of a Project Advisory Committee. Following an initial consultation with the Aboriginal community, Phase-II will invite community members to participate in co-design workshops. In Phase-III, the Chief Investigators will participate in co-design workshops and document generated ideas. The notes shall be analysed thematically in Phase-IV with Aboriginal community representatives, and the summary will be disseminated to the communities. In Phase-V, we will evaluate the co-design process and adapt our protocol for the use in partnership with other communities. (3) Discussion: This study protocol represents a crucial first step to ensure that PM research is relevant and acceptable to Aboriginal Australians. Without fair access to PM, the gap in health outcome between Aboriginal and non-Aboriginal Australians will continue to widen.
The impact of genomics on the future of medicine and health.
Publisher: AMPCo
Date: 07-2014
DOI: 10.5694/MJA13.10920
The Long Noncoding RNA SPRIGHTLY Regulates Cell Proliferation in Primary Human Melanocytes
Publisher: Elsevier BV
Date: 04-2016
The role of microRNAs and long non-coding RNAs in the pathology, diagnosis, and management of melanoma
Publisher: Elsevier BV
Date: 12-2014
Response to Brodehl et al.
Publisher: Elsevier BV
Date: 05-2018
Genome-wide discovery of human splicing branchpoints
Publisher: Cold Spring Harbor Laboratory
Date: 05-01-2015
Abstract: During the splicing reaction, the 5′ intron end is joined to the branchpoint nucleotide, selecting the next exon to incorporate into the mature RNA and forming an intron lariat, which is excised. Despite a critical role in gene splicing, the locations and features of human splicing branchpoints are largely unknown. We use exoribonuclease digestion and targeted RNA-sequencing to enrich for sequences that traverse the lariat junction and, by split and inverted alignment, reveal the branchpoint. We identify 59,359 high-confidence human branchpoints in ,000 genes, providing a first map of splicing branchpoints in the human genome. Branchpoints are predominantly adenosine, highly conserved, and closely distributed to the 3′ splice site. Analysis of human branchpoints reveals numerous novel features, including distinct features of branchpoints for alternatively spliced exons and a family of conserved sequence motifs overlapping branchpoints we term B-boxes, which exhibit maximal nucleotide ersity while maintaining interactions with the keto-rich U2 snRNA. Different B-box motifs exhibit ergent usage in vertebrate lineages and associate with other splicing elements and distinct intron–exon architectures, suggesting integration within a broader regulatory splicing code. Lastly, although branchpoints are refractory to common mutational processes and genetic variation, mutations occurring at branchpoint nucleotides are enriched for disease associations.
Mutations in the exocyst component EXOC2 cause severe defects in human brain development
Publisher: Rockefeller University Press
Date: 08-07-2020
DOI: 10.1084/JEM.20192040
Abstract: The exocyst, an octameric protein complex, is an essential component of the membrane transport machinery required for tethering and fusion of vesicles at the plasma membrane. We report pathogenic variants in an exocyst subunit, EXOC2 (Sec5). Affected in iduals have severe developmental delay, dysmorphism, and brain abnormalities variability associated with epilepsy and poor motor skills. Family 1 had two offspring with a homozygous truncating variant in EXOC2 that leads to nonsense-mediated decay of EXOC2 transcript, a severe reduction in exocytosis and vesicle fusion, and undetectable levels of EXOC2 protein. The patient from Family 2 had a milder clinical phenotype and reduced exocytosis. Cells from both patients showed defective Arl13b localization to the primary cilium. The discovery of mutations that partially disable exocyst function provides valuable insight into this essential protein complex in neural development. Since EXOC2 and other exocyst complex subunits are critical to neuronal function, our findings suggest that EXOC2 variants are the cause of the patients’ neurological disorders.
Quantitative gene profiling of long noncoding RNAs with targeted RNA sequencing
Publisher: Springer Science and Business Media LLC
Date: 09-03-2015
DOI: 10.1038/NMETH.3321
Abstract: We compared quantitative RT-PCR (qRT-PCR), RNA-seq and capture sequencing (CaptureSeq) in terms of their ability to assemble and quantify long noncoding RNAs and novel coding exons across 20 human tissues. CaptureSeq was superior for the detection and quantification of genes with low expression, showed little technical variation and accurately measured differential expression. This approach expands and refines previous annotations and simultaneously generates an expression atlas.
Dynamic expression of long noncoding RNAs and repeat elements in synaptic plasticity.
Publisher: Frontiers Media SA
Date: 10-2015
Novel aberrations uncovered in Barrett's esophagus and esophageal adenocarcinoma using whole transcriptome sequencing
Publisher: American Association for Cancer Research (AACR)
Date: 31-10-2017
DOI: 10.1158/1541-7786.MCR-17-0332
Abstract: Esophageal adenocarcinoma (EAC) has one of the fastest increases in incidence of any cancer, along with poor five-year survival rates. Barrett's esophagus (BE) is the main risk factor for EAC however, the mechanisms driving EAC development remain poorly understood. Here, transcriptomic profiling was performed using RNA-sequencing (RNA-seq) on premalignant and malignant Barrett's tissues to better understand this disease. Machine-learning and network analysis methods were applied to discover novel driver genes for EAC development. Identified gene expression signatures for the distinction of EAC from BE were validated in separate datasets. An extensive analysis of the noncoding RNA (ncRNA) landscape was performed to determine the involvement of novel transcriptomic elements in Barrett's disease and EAC. Finally, transcriptomic mutational investigation of genes that are recurrently mutated in EAC was performed. Through these approaches, novel driver genes were discovered for EAC, which involved key cell cycle and DNA repair genes, such as BRCA1 and PRKDC. A novel 4-gene signature (CTSL, COL17A1, KLF4, and E2F3) was identified, externally validated, and shown to provide excellent distinction of EAC from BE. Furthermore, expression changes were observed in 685 long noncoding RNAs (lncRNA) and a systematic dysregulation of repeat elements across different stages of Barrett's disease, with wide-ranging downregulation of Alu elements in EAC. Mutational investigation revealed distinct pathways activated between EAC tissues with or without TP53 mutations compared with Barrett's disease. In summary, transcriptome sequencing revealed altered expression of numerous novel elements, processes, and networks in EAC and premalignant BE. Implications: This study identified opportunities to improve early detection and treatment of patients with BE and esophageal adenocarcinoma. Mol Cancer Res 15(11) 1558–69. ©2017 AACR.
The regulatory role of long noncoding RNAs in cancer
Publisher: Elsevier BV
Date: 04-2017
DOI: 10.1016/J.CANLET.2017.01.010
Abstract: With the advances in genomic analysis technologies, especially next-generation RNA sequencing, a large number of new transcripts have been discovered, leading to better understanding of long noncoding RNAs (lncRNAs). Recent investigations have provided firm evidence for the critical roles of lncRNAs in chromatin modification, gene transcription, RNA splicing, RNA transport and translation. In vitro and in vivo studies have also proven that aberrant lncRNA expression is essential for the initiation and progression of cancers. Due to their unique tissue- and cancer-specific expression profiles, aberrant expression of lncRNAs can be used as reliable prognostic markers for cancer diagnoses and treatment stratification, and lncRNAs are novel therapeutic targets with high therapeutic windows.
Overcoming challenges and dogmas to understand the functions of pseudogenes
Publisher: Springer Science and Business Media LLC
Date: 17-12-2020
DOI: 10.1038/S41576-019-0196-1
Abstract: Pseudogenes are defined as regions of the genome that contain defective copies of genes. They exist across almost all forms of life, and in mammalian genomes are annotated in similar numbers to recognized protein-coding genes. Although often presumed to lack function, growing numbers of pseudogenes are being found to play important biological roles. In consideration of their evolutionary origins and inherent limitations in genome annotation practices, we posit that pseudogenes have been classified on a scientifically unsubstantiated basis. We reflect that a broad misunderstanding of pseudogenes, perpetuated in part by the pejorative inference of the 'pseudogene' label, has led to their frequent dismissal from functional assessment and exclusion from genomic analyses. With the advent of technologies that simplify the study of pseudogenes, we propose that an objective reassessment of these genomic elements will reveal valuable insights into genome function and evolution.
Non-coding RNAs in homeostasis, disease and stress responses: an evolutionary perspective.
Publisher: Oxford University Press (OUP)
Date: 05-2013
DOI: 10.1093/BFGP/ELT016
Abstract: Cells and organisms are subject to challenges and perturbations in their environment and physiology in all stages of life. The molecular response to such changes, including insulting conditions such as pathogen infections, involves coordinated modulation of gene expression programmes and has not only homeostatic but also ecological and evolutionary importance. Although attention has been primarily focused on signalling pathways and protein networks, non-coding RNAs (ncRNAs), which comprise a significant output of the genomes of prokaryotes and especially eukaryotes, are increasingly implicated in the molecular mechanisms of these responses. Long and short ncRNAs not only regulate development and cell physiology, they are also involved in disease states, including cancers, in host-pathogen interactions, and in a variety of stress responses. Indeed, regulatory RNAs are part of genetically encoded response networks and also underpin epigenetic processes, which are emerging as key mechanisms of adaptation and transgenerational inheritance. Here we present the growing evidence that ncRNAs are intrinsically involved in cellular and organismal adaptation processes, in both robustness and protection to stresses, as well as in mechanisms generating evolutionary change.
Genomic stratification and liquid biopsy in a rare adrenocortical carcinoma (ACC) case, with dual lung metastases
Publisher: Cold Spring Harbor Laboratory
Date: 04-2019
DOI: 10.1101/MCS.A003764
Abstract: Adrenocortical carcinoma is a rare malignancy with a poor prognosis and few treatment options. Molecular characterization of this cancer remains limited. We present a case of an adrenocortical carcinoma (ACC) in a 37-yr-old female, with dual lung metastases identified 1 yr following commencement of adjuvant mitotane therapy. As standard therapeutic regimens are often unsuccessful in ACC, we undertook a comprehensive genomic study into this case to identify treatment options and monitor disease progress. We performed targeted and whole-genome sequencing of germline, primary tumor, and both metastatic tumors from this patient and monitored recurrence over 2 years using liquid biopsy for ctDNA and steroid hormone measurements. Sequencing revealed the primary and metastatic tumors were hyperhaploid, with extensive loss of heterozygosity but few structural rearrangements. Loss-of-function mutations were identified in MSH2 , TP53 , RB1 , and PTEN , resulting in tumors with mismatch repair signatures and microsatellite instability. At the cellular level, tumors were populated by mitochondria-rich oncocytes. Longitudinal ctDNA mutation and hormone profiles were unable to detect micrometastatic disease, consistent with clinical indicators of disease remission. The molecular signatures in our ACC case suggested immunotherapy in the event of disease progression however, the patient remains free of cancer. The extensive molecular analysis presented here could be applied to other rare and/or poorly stratified cancers to identify novel or repurpose existing therapeutic options, thereby broadly improving diagnoses, treatments, and prognoses.
Use of Whole-Genome Sequencing for Mitochondrial Disease Diagnosis
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 16-08-2022
DOI: 10.1212/WNL.0000000000200745
Abstract: Mitochondrial diseases (MDs) are the commonest group of heritable metabolic disorders. Phenotypic ersity can make molecular diagnosis challenging, and causative genetic variants may reside in either mitochondrial or nuclear DNA. A single comprehensive genetic diagnostic test would be highly useful and transform the field. We applied whole-genome sequencing (WGS) to evaluate the variant detection rate and diagnostic capacity of this technology with a view to simplifying and improving the MD diagnostic pathway. Adult patients presenting to a specialist MD clinic in Sydney, Australia, were recruited to the study if they satisfied clinical MD (Nijmegen) criteria. WGS was performed on blood DNA, followed by clinical genetic analysis for known pathogenic MD-associated variants and MD mimics. Of the 242 consecutive patients recruited, 62 participants had “definite,” 108 had “probable,” and 72 had “possible” MD classification by the Nijmegen criteria. Disease-causing variants were identified for 130 participants, regardless of the location of the causative genetic variants, giving an overall diagnostic rate of 53.7% (130 of 242). Identification of causative genetic variants informed precise treatment, restored reproductive confidence, and optimized clinical management of MD. Comprehensive bigenomic sequencing accurately detects causative genetic variants in affected MD patients, simplifying diagnosis, enabling early treatment, and informing the risk of genetic transmission.
Archaeal genome organization and stress responses: implications for the origin and evolution of cellular life.
Publisher: Mary Ann Liebert Inc
Date: 08-2002
DOI: 10.1089/153110702762027835
Abstract: For DNA to be used as an informational molecule it must exist in the cell on the edge of stability because all genomic processes require local controlled melting. This presents mechanistic opportunities and problems for genomic DNA from hyperthermophilic organisms, whose unpackaged DNA could melt at optimal temperatures for growth. Hyperthermophiles are suggested to employ the novel positively supercoiling topoisomerase enzyme reverse gyrase (RG) to form positively supercoiled DNA that is intrinsically resistant to thermal denaturation. RG is presently the only archaeal gene that is uniquely found in hyperthermophiles and therefore is central to hypotheses suggesting a hypothermophilic origin of life. However, the suggestion that RG has evolved by the fusion of two pre-existing enzymes has led to hypotheses for a lower temperature for the origin of life. In addition to the action of topoisomerases, DNA packaging and the intracellular ionic environment can also manipulate DNA topology significantly. In the Euryarchaeota, nucleosomes containing minimal histones can adopt two alternate DNA topologies in a salt-dependent manner. From this we hypothesize that since internal salt concentrations are increased following an increase in temperature, the genomic effects of temperature fluctuations could also be accommodated by changes in nucleosome organization. In addition, stress-induced changes in the nucleoid proteins could also play a role in maintaining the genome in the optimal topological state in changing environments. The function of these systems could therefore be central to temperature adaptation and thus be implicated in origin of life scenarios involving hyperthermophiles.
RNAcentral: A vision for an international database of RNA sequences
Publisher: Cold Spring Harbor Laboratory
Date: 22-09-2011
DOI: 10.1261/RNA.2750811
Abstract: During the last decade there has been a great increase in the number of noncoding RNA genes identified, including new classes such as microRNAs and piRNAs. There is also a large growth in the amount of experimental characterization of these RNA components. Despite this growth in information, it is still difficult for researchers to access RNA data, because key data resources for noncoding RNAs have not yet been created. The most pressing omission is the lack of a comprehensive RNA sequence database, much like UniProt, which provides a comprehensive set of protein knowledge. In this article we propose the creation of a new open public resource that we term RNAcentral, which will contain a comprehensive collection of RNA sequences and fill an important gap in the provision of biomedical databases. We envision RNA researchers from all over the world joining a federated RNAcentral network, contributing specialized knowledge and databases. RNAcentral would centralize key data that are currently held across a variety of databases, allowing researchers instant access to a single, unified resource. This resource would facilitate the next generation of RNA research and help drive further discoveries, including those that improve food production and human and animal health. We encourage additional RNA database resources and research groups to join this effort. We aim to obtain international network funding to further this endeavor.
Whole genome sequencing provides better diagnostic yield and future value than whole exome sequencing the integration of genome sequencing with clinical records and data from the internet of things will transform health care
Publisher: AMPCo
Date: 09-04-2018
DOI: 10.5694/MJA17.01176
Dysregulation of non-coding RNAs in Rheumatoid arthritis
Publisher: Elsevier BV
Date: 10-2020
The evolution of RNAs with multiple functions.
Publisher: Elsevier BV
Date: 11-2011
DOI: 10.1016/J.BIOCHI.2011.07.018
Abstract: Increasing numbers of transcripts have been reported to transmit both protein-coding and regulatory information. Apart from challenging our conception of the gene, this observation raises the question as to what extent this phenomenon occurs across the genome and how and why such dual encoding of function has evolved in the eukaryotic genome. To address this question, we consider the evolutionary path of genes in the earliest forms of life on Earth, where it is generally regarded that proteins evolved from a cellular machinery based entirely within RNA. This led to the domination of protein-coding genes in the genomes of microorganisms, although it is likely that RNA never lost its other capacities and functionalities, as evidenced by cis-acting riboswitches and UTRs. On the basis that the subsequent evolution of a more sophisticated regulatory architecture to provide higher levels of epigenetic control and accurate spatiotemporal expression in developmentally complex organisms is a complicated task, we hypothesize: (i) that mRNAs have been and remain subject to secondary selection to provide trans-acting regulatory capability in parallel with protein-coding functions (ii) that some and perhaps many protein-coding loci, possibly as a consequence of gene duplication, have lost protein-coding functions en route to acquiring more sophisticated trans-regulatory functions (iii) that many transcripts have become subject to secondary processing to release different products and (iv) that novel proteins have emerged within loci that previously evolved functionality as regulatory RNAs. In support of the idea that there is a dynamic flux between different types of informational RNAs in both evolutionary and real time, we review recent observations that have arisen from transcriptomic surveys of complex eukaryotes and reconsider how these observations impact on the notion that apparently discrete loci may express transcripts with more than one function. In conclusion, we posit that many eukaryotic loci have evolved the capacity to transact a multitude of overlapping and potentially independent functions as both regulatory and protein-coding RNAs.
Global analysis of the mammalian RNA degradome reveals widespread miRNA-dependent and miRNA-independent endonucleolytic cleavage
Publisher: Oxford University Press (OUP)
Date: 22-03-2011
DOI: 10.1093/NAR/GKR110
The long noncoding RNA lncNB1 promotes tumorigenesis by interacting with ribosomal protein RPL35
Publisher: Springer Science and Business Media LLC
Date: 05-11-2019
DOI: 10.1038/S41467-019-12971-3
Abstract: The majority of patients with neuroblastoma due to MYCN oncogene lification and consequent N-Myc oncoprotein over-expression die of the disease. Here our analyses of RNA sequencing data identify the long noncoding RNA lncNB1 as one of the transcripts most over-expressed in MYCN - lified, compared with MYCN -non- lified, human neuroblastoma cells and also the most over-expressed in neuroblastoma compared with all other cancers. lncNB1 binds to the ribosomal protein RPL35 to enhance E2F1 protein synthesis, leading to DEPDC1B gene transcription. The GTPase-activating protein DEPDC1B induces ERK protein phosphorylation and N-Myc protein stabilization. Importantly, lncNB1 knockdown abolishes neuroblastoma cell clonogenic capacity in vitro and leads to neuroblastoma tumor regression in mice, while high levels of lncNB1 and RPL35 in human neuroblastoma tissues predict poor patient prognosis. This study therefore identifies lncNB1 and its binding protein RPL35 as key factors for promoting E2F1 protein synthesis, N-Myc protein stability and N-Myc-driven oncogenesis, and as therapeutic targets.
Effects of a Novel Long Noncoding RNA, lncUSMycN, on N-Myc Expression and Neuroblastoma Progression
Publisher: Oxford University Press (OUP)
Date: 06-2014
DOI: 10.1093/JNCI/DJU113
Abstract: Patients with neuroblastoma due to the lification of a 130-kb genomic DNA region containing the MYCN oncogene have poor prognoses. Bioinformatics data were used to discover a novel long noncoding RNA, lncUSMycN, at the 130-kb licon. RNA-protein pull-down assays were used to identify proteins bound to lncUSMycN RNA. Kaplan-Meier survival analysis, multivariable Cox regression, and two-sided log-rank test were used to examine the prognostic value of lncUSMycN and NonO expression in three cohorts of neuroblastoma patients (n = 47, 88, and 476, respectively). Neuroblastoma-bearing mice were treated with antisense oligonucleotides targeting lncUSMycN (n = 12) or mismatch sequence (n = 13), and results were analyzed by multiple comparison two-way analysis of variance. All statistical tests were two-sided. Bioinformatics data predicted lncUSMycN gene and RNA, and reverse-transcription polymerase chain reaction confirmed its three exons and two introns. The lncUSMycN gene was co lified with MYCN in 88 of 341 human neuroblastoma tissues. lncUSMycN RNA bound to the RNA-binding protein NonO, leading to N-Myc RNA upregulation and neuroblastoma cell proliferation. High levels of lncUSMycN and NonO expression in human neuroblastoma tissues independently predicted poor patient prognoses (lncUSMycN: hazard ratio [HR] = 1.87, 95% confidence interval [CI] = 1.06 to 3.28, P = .03 NonO: HR = 2.48, 95% CI = 1.34 to 4.57, P = .004). Treatment with antisense oligonucleotides targeting lncUSMycN in neuroblastoma-bearing mice statistically significantly hindered tumor progression (P < .001). Our data demonstrate the important roles of lncUSMycN and NonO in regulating N-Myc expression and neuroblastoma oncogenesis and provide the first evidence that lification of long noncoding RNA genes can contribute to tumorigenesis.
Whole-genome sequencing overcomes pseudogene homology to diagnose autosomal dominant polycystic kidney disease.
Publisher: Springer Science and Business Media LLC
Date: 11-05-2016
DOI: 10.1038/EJHG.2016.48
Long non-coding RNAs: definitions, functions, challenges and recommendations
Publisher: Springer Science and Business Media LLC
Date: 03-01-2023
Long noncoding RNAs in cancer: Mechanisms of action and technological advancements
Publisher: Springer Science and Business Media LLC
Date: 27-05-2016
Perspectives on the Role of Non-Coding RNAs in the Regulation of Expression and Function of the Estrogen Receptor
Publisher: MDPI AG
Date: 04-08-2020
Abstract: Estrogen receptors (ERs) comprise several nuclear and membrane-bound receptors with different tissue-specific functions. ERα and ERβ are two nuclear members of this family, whereas G protein-coupled estrogen receptor (GPER), ER-X, and Gq-coupled membrane estrogen receptor (Gq-mER) are membrane-bound G protein-coupled proteins. ERα participates in the development and function of several body organs such as the reproductive system, brain, heart and musculoskeletal systems. ERβ has a highly tissue-specific expression pattern, particularly in the female reproductive system, and exerts tumor-suppressive roles in some tissues. Recent studies have revealed functional links between both nuclear and membrane-bound ERs and non-coding RNAs. Several oncogenic lncRNAs and miRNAs have been shown to exert their effects through the modulation of the expression of ERs. Moreover, treatment with estradiol has been shown to alter the malignant behavior of cancer cells through functional axes composed of non-coding RNAs and ERs. The interaction between ERs and non-coding RNAs has functional relevance in several human pathologies associated with estrogen regulation, such as cancers, intervertebral disc degeneration, coronary heart disease and diabetes. In the current review, we summarize scientific literature on the role of miRNAs and lncRNAs on ER-associated signaling and related disorders.
Erratum
Publisher: Oxford University Press (OUP)
Date: 29-10-2014
DOI: 10.1093/JNCI/DJU359
Expression and Function of the Protein Tyrosine Phosphatase Receptor J (PTPRJ) in Normal Mammary Epithelial Cells and Breast Tumors
Publisher: Public Library of Science (PLoS)
Date: 17-07-2012
RNAs as extracellular signaling molecules
Publisher: Bioscientifica
Date: 16-01-2008
DOI: 10.1677/JME-07-0160
Abstract: RNA is emerging as a major component of the regulatory circuitry that underpins the development and physiology of complex organisms. Here we review recent evidence that suggests that RNA may supplement endocrine and paracrine signaling by small molecules and proteins, and act as an efficient and evolutionarily flexible source of sequence-specific information transfer between cells, both locally and systemically. As such, RNA signaling may play a central but previously hidden role in multicellular ontogeny, homeostasis, and transmitted epigenetic memory.
Saccharopolyspora erythraea’sgenome is organised in high-order transcriptional regions mediated by targeted degradation at the metabolic switch
Publisher: Springer Science and Business Media LLC
Date: 16-01-2013
Abstract: Actinobacteria form a major bacterial phylum that includes numerous human pathogens. Actinobacteria are primary contributors to carbon cycling and also represent a primary source of industrial high value products such as antibiotics and biopesticides. Consistent with other members of the actinobacterial phylum, Saccharopolyspora erythraea undergo a transitional switch. This switch is characterized by numerous metabolic and morphological changes. We performed RNA sequencing to analyze the transcriptional changes that occur during growth of Saccharopolyspora erythraea in batch culture. By sequencing RNA across the fermentation time course, at a mean coverage of 4000X, we found the vast majority of genes to be prominently expressed, showing that we attained close to saturating sequencing coverage of the transcriptome. During the metabolic switch, global changes in gene expression influence the metabolic machinery of Saccharopolyspora erythraea, resetting an entirely novel gene expression program. After the switch, global changes include the broad repression of half the genes regulated by complex transcriptional mechanisms. Paralogous transposon clusters, delineate these transcriptional programs. The new transcriptional program is orchestrated by a bottleneck event during which mRNA levels are severely restricted by targeted mRNA degradation. Our results, which attained close to saturating sequencing coverage of the transcriptome, revealed unanticipated transcriptional complexity with almost one third of transcriptional content originating from un-annotated sequences. We showed that the metabolic switch is a sophisticated mechanism of transcriptional regulation capable of resetting and re-synchronizing gene expression programs at extraordinary speed and scale.
Differentiating protein-coding and noncoding RNA: Challenges and ambiguities
Publisher: Public Library of Science (PLoS)
Date: 28-11-2008
The Functional Characterization of Long Noncoding RNASPRY4-IT1in Human Melanoma Cells
Publisher: Impact Journals, LLC
Date: 26-03-2014
Abstract: Expression of the long noncoding RNA (lncRNA) SPRY4-IT1 is low in normal human melanocytes but high in melanoma cells. siRNA knockdown of SPRY4-IT1 blocks melanoma cell invasion and proliferation, and increases apoptosis. To investigate its function further, we affinity purified SPRY4-IT1 from melanoma cells and used mass spectrometry to identify the protein lipin 2, an enzyme that converts phosphatidate to diacylglycerol (DAG), as a major binding partner. SPRY4-IT1 knockdown increases the accumulation of lipin2 protein and upregulate the expression of diacylglycerol O-acyltransferase 2 (DGAT2) an enzyme involved in the conversion of DAG to triacylglycerol (TAG). When SPRY4-IT1 knockdown and control melanoma cells were subjected to shotgun lipidomics, an MS-based assay that permits the quantification of changes in the cellular lipid profile, we found that SPRY4-IT1 knockdown induced significant changes in a number of lipid species, including increased acyl carnitine, fatty acyl chains, and triacylglycerol (TAG). Together, these results suggest the possibility that SPRY4-IT1 knockdown may induce apoptosis via lipin 2-mediated alterations in lipid metabolism leading to cellular lipotoxicity.
Supplementary Data from Lipid Uptake Is an Androgen-Enhanced Lipid Supply Pathway Associated with Prostate Cancer Disease Progression and Bone Metastasis
Publisher: American Association for Cancer Research (AACR)
Date: 03-04-2023
DOI: 10.1158/1541-7786.22513434
Abstract: Supplementary Figures
RNAdb 2.0--an expanded database of mammalian non-coding RNAs
Publisher: Oxford University Press (OUP)
Date: 03-01-2007
DOI: 10.1093/NAR/GKL926
RNA-seq reveals more consistent reference genes for gene expression studies in human non-melanoma skin cancers
Publisher: PeerJ
Date: 21-08-2017
DOI: 10.7717/PEERJ.3631
Abstract: Identification of appropriate reference genes (RGs) is critical to accurate data interpretation in quantitative real-time PCR (qPCR) experiments. In this study, we have utilised next generation RNA sequencing (RNA-seq) to analyse the transcriptome of a panel of non-melanoma skin cancer lesions, identifying genes that are consistently expressed across all s les. Genes encoding ribosomal proteins were amongst the most stable in this dataset. Validation of this RNA-seq data was examined using qPCR to confirm the suitability of a set of highly stable genes for use as qPCR RGs. These genes will provide a valuable resource for the normalisation of qPCR data for the analysis of non-melanoma skin cancer.
Genome-wide methylated CpG island profiles of melanoma cells reveal a melanoma coregulation network
Publisher: Springer Science and Business Media LLC
Date: 16-10-2013
DOI: 10.1038/SREP02962
Abstract: Metastatic melanoma is a malignant cancer with generally poor prognosis, with no targeted chemotherapy. To identify epigenetic changes related to melanoma, we have determined genome-wide methylated CpG island distributions by next-generation sequencing. Melanoma chromosomes tend to be differentially methylated over short CpG island tracts. CpG islands in the upstream regulatory regions of many coding and noncoding RNA genes, including, for ex le, TERC , which encodes the telomerase RNA, exhibit extensive hypermethylation, whereas several repeated elements, such as LINE 2 and several LTR elements, are hypomethylated in advanced stage melanoma cell lines. By using CpG island demethylation profiles and by integrating these data with RNA-seq data obtained from melanoma cells, we have identified a co-expression network of differentially methylated genes with significance for cancer related functions. Focused assays of melanoma patient tissue s les for CpG island methylation near the noncoding RNA gene SNORD-10 demonstrated high specificity.
The Evx1/Evx1as gene locus regulates anterior-posterior patterning during gastrulation.
Publisher: Springer Science and Business Media LLC
Date: 26-05-2016
DOI: 10.1038/SREP26657
Abstract: Thousands of sense-antisense mRNA-lncRNA gene pairs occur in the mammalian genome. While there is usually little doubt about the function of the coding transcript, the function of the lncRNA partner is mostly untested. Here we examine the function of the homeotic Evx1 - Evx1as gene locus. Expression is tightly co-regulated in posterior mesoderm of mouse embryos and in embryoid bodies. Expression of both genes is enhanced by BMP4 and WNT3A, and reduced by Activin. We generated a suite of deletions in the locus by CRISPR-Cas9 editing. We show EVX1 is a critical downstream effector of BMP4 and WNT3A with respect to patterning of posterior mesoderm. The lncRNA, Evx1as arises from alternative promoters and is difficult to fully abrogate by gene editing or siRNA approaches. Nevertheless, we were able to generate a large 2.6 kb deletion encompassing the shared promoter with Evx1 and multiple additional exons of Evx1as. This led to an identical dorsal-ventral patterning defect to that generated by micro-deletion in the DNA-binding domain of EVX1. Thus, Evx1as has no function independent of EVX1, and is therefore unlikely to act in trans . We predict many antisense lncRNAs have no specific trans function, possibly only regulating the linked coding genes in cis .
The retroelement Lx9 puts a brake on the immune response to virus infection
Publisher: Springer Science and Business Media LLC
Date: 10-08-2022
DOI: 10.1038/S41586-022-05054-9
Abstract: The notion that mobile units of nucleic acid known as transposable elements can operate as genomic controlling elements was put forward over six decades ago
A Mild PUM1 Mutation Is Associated with Adult-Onset Ataxia, whereas Haploinsufficiency Causes Developmental Delay and Seizures
Publisher: Elsevier BV
Date: 02-2018
Long noncoding RNAs in mouse embryonic stem cell pluripotency and differentiation
Publisher: Cold Spring Harbor Laboratory
Date: 18-06-2008
Abstract: The transcriptional networks that regulate embryonic stem (ES) cell pluripotency and lineage specification are the subject of considerable attention. To date such studies have focused almost exclusively on protein-coding transcripts. However, recent transcriptome analyses show that the mammalian genome contains thousands of long noncoding RNAs (ncRNAs), many of which appear to be expressed in a developmentally regulated manner. The functions of these remain untested. To identify ncRNAs involved in ES cell biology, we used a custom-designed microarray to examine the expression profiles of mouse ES cells differentiating as embryoid bodies (EBs) over a 16-d time course. We identified 945 ncRNAs expressed during EB differentiation, of which 174 were differentially expressed, many correlating with pluripotency or specific differentiation events. Candidate ncRNAs were identified for further characterization by an integrated examination of expression profiles, genomic context, chromatin state, and promoter analysis. Many ncRNAs showed coordinated expression with genomically associated developmental genes, such as Dlx1 , Dlx4 , Gata6 , and Ecsit . We examined two novel developmentally regulated ncRNAs, Evx1as and Hoxb5/6as , which are derived from homeotic loci and share similar expression patterns and localization in mouse embryos with their associated protein-coding genes. Using chromatin immunoprecipitation, we provide evidence that both ncRNAs are associated with trimethylated H3K4 histones and histone methyltransferase MLL1, suggesting a role in epigenetic regulation of homeotic loci during ES cell differentiation. Taken together, our data indicate that long ncRNAs are likely to be important in processes directing pluripotency and alternative differentiation programs, in some cases through engagement of the epigenetic machinery.
Comparison of whole-exome sequencing of matched fresh and formalin fixed paraffin embedded melanoma tumours: Implications for clinical decision making
Publisher: Elsevier BV
Date: 04-2016
DOI: 10.1016/J.PATHOL.2016.01.001
Abstract: The identification of recurrent driver mutations by whole-exome sequencing (WES) of fresh-frozen human cancers and the subsequent development of novel targeted therapies have recently transformed the treatment of many cancers including melanoma. In routine clinical practice, fresh-frozen tissue is rarely available and mutation testing usually needs to be carried out on archival formalin fixed, paraffin embedded (FFPE) tissue, from which DNA is typically fragmented, cross-linked and of lower quality. In this study we aimed to determine whether WES data generated from genomic DNA (gDNA) extracted from FFPE tissues can be produced reliably and of clinically-actionable standard. In this study of ten melanoma patients, we compared WES data produced from analysis of gDNA isolated from FFPE tumour tissue with that isolated from fresh-frozen tumour tissue from the same specimen. FFPE s les were sequenced using both Illumina's Nextera and NimbleGen SeqCap exome capture kits. To examine mutations between the two tissue sources and platforms, somatic mutations in the FFPE exomes were called using the matched fresh tissue sequence as a reference. Of the 10 FFPE DNA s les, seven Nextera and four SeqCap s les passed library preparation. On average, there were 5341 and 2246 variants lost in FFPE compared to matched fresh tissue utilising Nextera and SeqCap kits, respectively. In order to explore the feasibility of future clinical implementation of WES, FFPE variants in 27 genes of important clinical relevance in melanoma were assessed. The average concordance rate was 43.2% over a total of 1299 calls for the chosen genes in the FFPE DNA. For the current clinically most important melanoma mutations, 0/3 BRAF and 6/8 (75%) NRAS FFPE calls were concordant with the fresh tissue result, which was confirmed using a Sequenom OncoCarta Panel. The poor performance of FFPE WES indicates that specialised library construction to account for low quality DNA and further refinements will be necessary before this approach could be used for routine clinical decision making over currently preferred techniques.
The Reality of Pervasive Transcription
Publisher: Public Library of Science (PLoS)
Date: 12-07-2011
RNA regulation of epigenetic processes
Publisher: Wiley
Date: 2009
DOI: 10.1002/BIES.080099
Abstract: There is increasing evidence that dynamic changes to chromatin, chromosomes and nuclear architecture are regulated by RNA signalling. Although the precise molecular mechanisms are not well understood, they appear to involve the differential recruitment of a hierarchy of generic chromatin modifying complexes and DNA methyltransferases to specific loci by RNAs during differentiation and development. A significant fraction of the genome-wide transcription of non-protein coding RNAs may be involved in this process, comprising a previously hidden layer of intermediary genetic information that underpins developmental ontogeny and the differences between species, ecotypes and in iduals. It is also evident that RNA editing is a primary means by which hardwired genetic information in animals can be altered by environmental signals, especially in the brain, indicating a dynamic RNA-mediated interplay between the transcriptome, the environment and the epigenome. Moreover, RNA-directed regulatory processes may also transfer epigenetic information not only within cells but also between cells and organ systems, as well as across generations.
I-motif DNA structures are formed in the nuclei of human cells
Publisher: Springer Science and Business Media LLC
Date: 23-04-2018
DOI: 10.1038/S41557-018-0046-3
Abstract: Human genome function is underpinned by the primary storage of genetic information in canonical B-form DNA, with a second layer of DNA structure providing regulatory control. I-motif structures are thought to form in cytosine-rich regions of the genome and to have regulatory functions however, in vivo evidence for the existence of such structures has so far remained elusive. Here we report the generation and characterization of an antibody fragment (iMab) that recognizes i-motif structures with high selectivity and affinity, enabling the detection of i-motifs in the nuclei of human cells. We demonstrate that the in vivo formation of such structures is cell-cycle and pH dependent. Furthermore, we provide evidence that i-motif structures are formed in regulatory regions of the human genome, including promoters and telomeric regions. Our results support the notion that i-motif structures provide key regulatory roles in the genome.
Pregnancy-induced noncoding RNA (PINC) associates with polycomb repressive complex 2 and regulates mammary epithelial differentiation
Publisher: Public Library of Science (PLoS)
Date: 26-07-2012
High resolution temporal transcriptomics of mouse embryoid body development reveals complex expression dynamics of coding and noncoding loci
Publisher: Springer Science and Business Media LLC
Date: 27-07-2017
DOI: 10.1038/S41598-017-06110-5
Abstract: Cellular responses to stimuli are rapid and continuous and yet the vast majority of investigations of transcriptional responses during developmental transitions typically use long interval time courses limiting the available interpretive power. Moreover, such experiments typically focus on protein-coding transcripts, ignoring the important impact of long noncoding RNAs. We therefore evaluated coding and noncoding expression dynamics at unprecedented temporal resolution (6-hourly) in differentiating mouse embryonic stem cells and report new insight into molecular processes and genome organization. We present a highly resolved differentiation cascade that exhibits coding and noncoding transcriptional alterations, transcription factor network interactions and alternative splicing events, little of which can be resolved by long-interval developmental time-courses. We describe novel short lived and cycling patterns of gene expression and dissect temporally ordered gene expression changes in response to transcription factors. We elucidate patterns in gene co-expression across the genome, describe asynchronous transcription at bidirectional promoters and functionally annotate known and novel regulatory lncRNAs. These findings highlight the complex and dynamic molecular events underlying mammalian differentiation that can only be observed though a temporally resolved time course.
Gonadal mosaicism of a novel IQSEC2 variant causing female limited intellectual disability and epilepsy
Publisher: Springer Science and Business Media LLC
Date: 15-03-2017
DOI: 10.1038/EJHG.2017.29
High temporal resolution of gene expression dynamics in developing mouse embryonic stem cells
Publisher: Cold Spring Harbor Laboratory
Date: 31-10-2016
DOI: 10.1101/084442
Abstract: Investigations of transcriptional responses during developmental transitions typically use time courses with intervals that are not commensurate with the timescales of known biological processes. Moreover, such experiments typically focus on protein-coding transcripts, ignoring the important impact of long noncoding RNAs. We evaluated coding and noncoding expression dynamics at high temporal resolution (6-hourly) in differentiating mouse embryonic stem cells and report the effects of increased temporal resolution on the characterization of the underlying molecular processes. We present a refined resolution of global transcriptional alterations, including regulatory network interactions, coding and noncoding gene expression changes as well as alternative splicing events, many of which cannot be resolved by existing coarse developmental time--courses. We describe novel short lived and cycling patterns of gene expression and temporally dissect ordered gene expression at bidirectional promoters and responses to transcription factors. These findings demonstrate the importance of temporal resolution for understanding gene interactions in mammalian systems. Data has been deposited into GEO: The Reviewer access link is: eo/query/acc.cgi?token=cnglummejbkltyj@acc=GSE75028
Gonadotropin suppression in men leads to a reduction in claudin-11 at the Sertoli cell tight junction
Publisher: Oxford University Press (OUP)
Date: 18-02-2016
Abstract: Are Sertoli cell tight junctions (TJs) disrupted in men undergoing hormonal contraception? Localization of the key Sertoli cell TJ protein, claudin-11, was markedly disrupted by 8 weeks of gonadotropin suppression, the degree of which was related to the extent of adluminal germ cell suppression. Sertoli cell TJs are vital components of the blood-testis barrier (BTB) that sequester developing adluminal meiotic germ cells and spermatids from the vascular compartment. Claudin-11 knockout mice are infertile additionally claudin-11 is spatially disrupted in chronically gonadotropin-suppressed rats coincident with a loss of BTB function, and claudin-11 is disorganized in various human testicular disorders. These data support the Sertoli cell TJ as a potential site of hormonal contraceptive action. BTB proteins were assessed by immunohistochemistry (n = 16 s les) and mRNA (n = 18 s les) expression levels in available archived testis tissue from a previous study of 22 men who had undergone 8 weeks of gonadotropin suppression and for whom meiotic and post-meiotic germ cell numbers were available. The gonadotropin suppression regimens were (i) testosterone enanthate (TE) plus the GnRH antagonist, acyline (A) (ii) TE + the progestin, levonorgestrel, (LNG) (iii) TE + LNG + A or (iv) TE + LNG + the 5α-reductase inhibitor, dutasteride (D). A control group consisted of seven additional men, with three archived s les available for this study. Immunohistochemical localization of claudin-11 (TJ) and other junctional type markers [ZO-1 (cytoplasmic plaque), β-catenin (adherens junction), connexin-43 (gap junction), vinculin (ectoplasmic specialization) and β-actin (cytoskeleton)] and quantitative PCR was conducted using matched frozen testis tissue. Claudin-11 formed a continuous staining pattern at the BTB in control men. Regardless of gonadotropin suppression treatment, claudin-11 localization was markedly disrupted and was broadly associated with the extent of meiotic ost-meiotic germ cell suppression claudin-11 staining was (i) punctate (i.e. 'spotty' appearance) at the basal aspect of tubules when the average numbers of adluminal germ cells were 40% of control. Changes in localization of connexin-43 and vinculin were also observed (smaller effects than for claudin-11) but ZO-1, β-catenin and β-actin did not differ, compared with control. Claudin-11 was the only Sertoli cell TJ protein investigated, but it is considered to be the most pivotal of constituent proteins given its known implication in infertility and BTB function. We were limited to testis s les which had been gonadotropin-suppressed for 8 weeks, shorter than the 74-day spermatogenic wave, which may account for the heterogeneity in claudin-11 and germ cell response observed among the men. Longer suppression (12-24 weeks) is known to suppress germ cells further and claudin-11 disruption may be more uniform, although we could not access such s les. These findings are important for our understanding of the sites of action of male hormonal contraception, because they suggest that BTB function could be ablated following long-term hormone suppression treatment. National Health and Medical Research Council (Australia) Program Grants 241000 and 494802 Research Fellowship 1022327 (to R.I.M.) and the Victorian Government's Operational Infrastructure Support Program. None of the authors have any conflicts to disclose. Not applicable.
Long non-coding RNAs: Insights into functions
Publisher: Springer Science and Business Media LLC
Date: 03-2009
DOI: 10.1038/NRG2521
Abstract: In mammals and other eukaryotes most of the genome is transcribed in a developmentally regulated manner to produce large numbers of long non-coding RNAs (ncRNAs). Here we review the rapidly advancing field of long ncRNAs, describing their conservation, their organization in the genome and their roles in gene regulation. We also consider the medical implications, and the emerging recognition that any transcript, regardless of coding potential, can have an intrinsic function as an RNA.
Reanalysis and optimisation of bioinformatic pipelines is critical for mutation detection
Publisher: Hindawi Limited
Date: 31-01-2019
DOI: 10.1002/HUMU.23699
The specificity of long noncoding RNA expression
Publisher: Elsevier BV
Date: 2016
DOI: 10.1016/J.BBAGRM.2015.08.005
Abstract: Over the last decade, long noncoding RNAs (lncRNAs) have emerged as a fundamental molecular class whose members play pivotal roles in the regulation of the genome. The observation of pervasive transcription of mammalian genomes in the early 2000s sparked a revolution in the understanding of information flow in eukaryotic cells and the incredible flexibility and dynamic nature of the transcriptome. As a molecular class, distinct loci yielding lncRNAs are set to outnumber those yielding mRNAs. However, like many important discoveries, the road leading to uncovering this erse class of molecules that act through a remarkable repertoire of mechanisms, was not a straight one. The same characteristic that most distinguishes lncRNAs from mRNAs, i.e. their developmental-stage, tissue-, and cell-specific expression, was one of the major impediments to their discovery and recognition as potentially functional regulatory molecules. With growing numbers of lncRNAs being assigned to biological functions, the specificity of lncRNA expression is now increasingly recognized as a characteristic that imbues lncRNAs with great potential as biomarkers and for the development of highly targeted therapeutics. Here we review the history of lncRNA research and how technological advances and insight into biological complexity have gone hand-in-hand in shaping this revolution. We anticipate that as increasing numbers of these molecules, often described as the dark matter of the genome, are characterized and the structure-function relationship of lncRNAs becomes better understood, it may ultimately be feasible to decipher what these non-(protein)-coding genes encode. This article is part of a Special Issue entitled: Clues to long noncoding RNA taxonomy1, edited by Dr. Tetsuro Hirose and Dr. Shinichi Nakagawa.
Whole Genome Sequencing, Focused Assays and Functional Studies Increasing Understanding in Cryptic Inherited Retinal Dystrophies
Publisher: MDPI AG
Date: 31-03-2022
DOI: 10.3390/IJMS23073905
Abstract: The inherited retinal dystrophies (IRDs) are a clinically and genetically complex group of disorders primarily affecting the rod and cone photoreceptors or other retinal neuronal layers, with emerging therapies heralding the need for accurate molecular diagnosis. Targeted capture and panel-based strategies examining the partial or full exome deliver molecular diagnoses in many IRD families tested. However, approximately one in three families remain unsolved and unable to obtain personalised recurrence risk or access to new clinical trials or therapy. In this study, we investigated whole genome sequencing (WGS), focused assays and functional studies to assist with unsolved IRD cases and facilitate integration of these approaches to a broad molecular diagnostic clinical service. The WGS approach identified variants not covered or underinvestigated by targeted capture panel-based clinical testing strategies in six families. This included structural variants, with notable benefit of the WGS approach in repetitive regions demonstrated by a family with a hybrid gene and hemizygous missense variant involving the opsin genes, OPN1LW and OPN1MW. There was also benefit in investigation of the repetitive GC-rich ORF15 region of RPGR. Further molecular investigations were facilitated by focused assays in these regions. Deep intronic variants were identified in IQCB1 and ABCA4, with functional RNA based studies of the IQCB1 variant revealing activation of a cryptic splice acceptor site. While targeted capture panel-based methods are successful in achieving an efficient molecular diagnosis in a proportion of cases, this study highlights the additional benefit and clinical value that may be derived from WGS, focused assays and functional genomics in the highly heterogeneous IRDs.
RNAcentral: a hub of information for non-coding RNA sequences
Publisher: Oxford University Press (OUP)
Date: 05-11-2018
DOI: 10.1093/NAR/GKY1034
Evolutionary conservation of embryonic DNA methylome remodelling in distantly related teleost species
Publisher: Oxford University Press (OUP)
Date: 24-08-2023
DOI: 10.1093/NAR/GKAD695
Abstract: Methylation of cytosines in the CG context (mCG) is the most abundant DNA modification in vertebrates that plays crucial roles in cellular differentiation and identity. After fertilization, DNA methylation patterns inherited from parental gametes are remodelled into a state compatible with embryogenesis. In mammals, this is achieved through the global erasure and re-establishment of DNA methylation patterns. However, in non-mammalian vertebrates like zebrafish, no global erasure has been observed. To investigate the evolutionary conservation and ergence of DNA methylation remodelling in teleosts, we generated base resolution DNA methylome datasets of developing medaka and medaka-zebrafish hybrid embryos. In contrast to previous reports, we show that medaka display comparable DNA methylome dynamics to zebrafish with high gametic mCG levels (sperm: ∼90% egg: ∼75%), and adoption of a paternal-like methylome during early embryogenesis, with no signs of prior DNA methylation erasure. We also demonstrate that non-canonical DNA methylation (mCH) reprogramming at TGCT tandem repeats is a conserved feature of teleost embryogenesis. Lastly, we find remarkable evolutionary conservation of DNA methylation remodelling patterns in medaka-zebrafish hybrids, indicative of compatible DNA methylation maintenance machinery in far-related teleost species. Overall, these results suggest strong evolutionary conservation of DNA methylation remodelling pathways in teleosts, which is distinct from the global DNA methylome erasure and reestablishment observed in mammals.
Whole Genome Sequencing Improves Outcomes of Genetic Testing in Patients With Hypertrophic Cardiomyopathy
Publisher: Elsevier BV
Date: 07-2018
DOI: 10.1016/J.JACC.2018.04.078
Abstract: Whole genome sequencing (WGS) is a comprehensive genetic testing approach that reports most types of nucleotide variants. This study sought to assess WGS for hypertrophic cardiomyopathy (HCM) in which prior genetic testing did not establish a molecular diagnosis, and as a first-line genetic test. WGS was performed on 58 unrelated patients with HCM, 14 affected family members, and 2 unaffected parents of a severely affected proband. The authors searched for nucleotide variants in coding regions of 184 candidate cardiac hypertrophy genes. They also searched for nucleotide variants in deep intronic regions that alter RNA splicing, large genomic rearrangements, and mitochondrial genome variants. RNA analysis was performed to validate splice-altering variants. The authors found a pathogenic or likely pathogenic variant in 9 of 46 families (20%) for which prior genetic testing was inconclusive. Three families had variants in genes not included in prior genetic testing. One family had a pathogenic variant that was filtered out with prior exome sequencing. Five families had pathogenic variants in noncoding regions, including 4 with deep intronic variants that activate novel splicing, and 1 mitochondrial genome variant. As a first-line genetic test, WGS identified a pathogenic variant in 5 of 12 families (42%) that had never received prior genetic testing. WGS identified additional genetic causes of HCM over targeted gene sequencing approaches. Extending genetic screening to deep intronic regions identified pathogenic variants in 9% of gene-elusive HCM. These findings translate to more accurate diagnosis and management in HCM families.
IncRNAs: Finding the Forest Among the Trees?
Publisher: Elsevier BV
Date: 12-2011
DOI: 10.1038/MT.2011.251
De Novo Variants Disrupting the HX Repeat Motif of ATN1 Cause a Recognizable Non-progressive Neurocognitive Syndrome
Publisher: Elsevier BV
Date: 04-2019
Pinstripe: a suite of programs for integrating transcriptomic and proteomic datasets identifies novel proteins and improves differentiation of protein-coding and non-coding genes.
Publisher: Oxford University Press (OUP)
Date: 07-10-2012
DOI: 10.1093/BIOINFORMATICS/BTS582
Abstract: Motivation: Comparing transcriptomic data with proteomic data to identify protein-coding sequences is a long-standing challenge in molecular biology, one that is exacerbated by the increasing size of high-throughput datasets. To address this challenge, and thereby to improve the quality of genome annotation and understanding of genome biology, we have developed an integrated suite of programs, called Pinstripe. We demonstrate its application, utility and discovery power using transcriptomic and proteomic data from publicly available datasets. Results: To demonstrate the efficacy of Pinstripe for large-scale analysis, we applied Pinstripe’s reverse peptide mapping pipeline to a transcript library including de novo assembled transcriptomes from the human Illumina Body Atlas (IBA2) and GENCODE v10 gene annotations, and the EBI Proteomics Identifications Database (PRIDE) peptide database. This analysis identified 736 canonical open reading frames (ORFs) supported by three or more PRIDE peptide fragments that are positioned outside any known coding DNA sequence (CDS). Because of the unfiltered nature of the PRIDE database and high probability of false discovery, we further refined this list using independent evidence for translation, including the presence of a Kozak sequence or functional domains, synonymous/non-synonymous substitution ratios and ORF length. Using this integrative approach, we observed evidence of translation from a previously unknown let7e primary transcript, the archetypical lncRNA H19, and a homolog of RD3. Reciprocally, by exclusion of transcripts with mapped peptides or significant ORFs (& codon), we identify 32 187 loci with RNAs longer than 2000 nt that are unlikely to encode proteins. Availability and implementation: Pinstripe (pinstripe.matticklab.com) is freely available as source code or a Mono binary. Pinstripe is written in C# and runs under the Mono framework on Linux or Mac OS X, and both under Mono and .Net under Windows. Contact: m.dinger@garvan.org.au or j.mattick@garvan.org.au Supplementary information: Supplementary data are available at Bioinformatics online.
Identification of novel markers of mouse fetal ovary development
Publisher: Public Library of Science (PLoS)
Date: 26-07-2012
Cancer-associated noncoding mutations affect RNA G-quadruplex-mediated regulation of gene expression
Publisher: Springer Science and Business Media LLC
Date: 06-04-2017
DOI: 10.1038/S41598-017-00739-Y
Abstract: Cancer is a multifactorial disease driven by a combination of genetic and environmental factors. Many cancer driver mutations have been characterised in protein-coding regions of the genome. However, mutations in noncoding regions associated with cancer have been less investigated. G-quadruplex (G4) nucleic acids are four-stranded secondary structures formed in guanine-rich sequences and prevalent in the regulatory regions. In this study, we used published whole cancer genome sequence data to find mutations in cancer patients that overlap potential RNA G4-forming sequences in 5′ UTRs. Using RNAfold, we assessed the effect of these mutations on the thermodynamic stability of predicted RNA G4s in the context of full-length 5′ UTRs. Of the 217 identified mutations, we found that 33 are predicted to destabilise and 21 predicted to stabilise potential RNA G4s. We experimentally validated the effect of destabilising mutations in the 5′ UTRs of BCL2 and CXCL14 and one stabilising mutation in the 5′ UTR of TAOK2 . These mutations resulted in an increase or a decrease in translation of these mRNAs, respectively. These findings suggest that mutations that modulate the G4 stability in the noncoding regions could act as cancer driver mutations, which present an opportunity for early cancer diagnosis using in idual sequencing information.
Corrigendum: Dynamic expression of long noncoding RNAs and repeat elements in synaptic plasticity
Publisher: Frontiers Media SA
Date: 27-07-2016
Role and practice evolution for genetic counseling in the genomic era: The experience of Australian and UK genetics practitioners
Publisher: Wiley
Date: 15-12-2018
DOI: 10.1002/JGC4.1053
Abstract: Facilitating informed decision-making regarding genetic testing is a core component of genetic counseling practice. Internationally, genetic testing is shifting toward gene panels and genomic testing, including whole exome and whole genome sequencing to improve diagnostic yield and cost-effectiveness. This study explored genetics practitioners' current experience with panels and genomic tests and the associated evolution of genetic counseling practice. Genetics practitioners with genomic testing experience, were purposively invited to participate in a semi-structured telephone interview and to snowball the invitation to colleagues. Interviews conducted with participants residing in Australia (n = 9) and the UK (n = 5) were transcribed and analyzed using an inductive thematic approach. Three themes emerged: (a) Role delineation: current roles, future roles, and the influence of increasing complexity (b) The evolving spectrum of practice: blurred boundaries between research and clinical services impact on facilitation of informed consent and return of results strategies and (c) Policy and governance needs: equality of access achieving consistent variant interpretation, reporting, and responsibility for review managing incidental findings and professional regulation for Australian genetic counselors. These exploratory data highlight that genetic counseling practice and the essential role of facilitating informed consent are evolving but remain patient-centered, with core skills underpinning practitioners' capacity to adapt.
Seave: a comprehensive web platform for storing and interrogating human genomic variation
Publisher: Cold Spring Harbor Laboratory
Date: 31-01-2018
DOI: 10.1101/258061
Abstract: Capability for genome sequencing and variant calling has increased dramatically, enabling large scale genomic interrogation of human disease. However, discovery is hindered by the current limitations in genomic interpretation, which remains a complicated and disjointed process. We introduce Seave, a web platform that enables variants to be easily filtered and annotated with in silico pathogenicity prediction scores and annotations from popular disease databases. Seave stores genomic variation of all types and sizes, and allows filtering for specific inheritance patterns, quality values, allele frequencies and gene lists. Seave is open source and deployable locally, or on a cloud computing provider, and works readily with gene panel, exome and whole genome data, scaling from single labs to multi-institution scale.
Pervasive transcription of the eukaryotic genome: Functional indices and conceptual implications
Publisher: Oxford University Press (OUP)
Date: 21-09-2009
DOI: 10.1093/BFGP/ELP038
Abstract: Genome-wide analyses of the eukaryotic transcriptome have revealed that the majority of the genome is transcribed, producing large numbers of non-protein-coding RNAs (ncRNAs). This surprising observation challenges many assumptions about the genetic programming of higher organisms and how information is stored and organized within the genome. Moreover, the rapid advances in genomics have given little opportunity for biologists to integrate these emerging findings into their intellectual and experimental frameworks. This problem has been compounded by the perception that genome-wide studies often generate more questions than answers, which in turn has led to confusion and controversy. In this article, we address common questions associated with the phenomenon of pervasive transcription and consider the indices that can be used to evaluate the function (or lack thereof) of the resulting ncRNAs. We suggest that many lines of evidence, including expression profiles, conservation signatures, chromatin modification patterns and examination of increasing numbers of in idual cases, argue in favour of the widespread functionality of non-coding transcription. We also discuss how informatic and experimental approaches used to analyse protein-coding genes may not be applicable to ncRNAs and how the general perception that protein-coding genes form the main informational output of the genome has resulted in much of the misunderstanding surrounding pervasive transcription and its potential significance. Finally, we present the conceptual implications of the majority of the eukaryotic genome being functional and describe how appreciating this perspective will provide considerable opportunity to further understand the molecular basis of development and complex diseases.
Denisovan, modern human and mouse TNFAIP3 alleles tune A20 phosphorylation and immunity
Publisher: Springer Science and Business Media LLC
Date: 18-09-2019
DOI: 10.1038/S41590-019-0492-0
Abstract: Resisting and tolerating microbes are alternative strategies to survive infection, but little is known about the evolutionary mechanisms controlling this balance. Here genomic analyses of anatomically modern humans, extinct Denisovan hominins and mice revealed a TNFAIP3 allelic series with alterations in the encoded immune response inhibitor A20. Each TNFAIP3 allele encoded substitutions at non-catalytic residues of the ubiquitin protease OTU domain that diminished IκB kinase-dependent phosphorylation and activation of A20. Two TNFAIP3 alleles encoding A20 proteins with partial phosphorylation deficits seemed to be beneficial by increasing immunity without causing spontaneous inflammatory disease: A20 T108A I207L, originating in Denisovans and introgressed in modern humans throughout Oceania, and A20 I325N, from an N-ethyl-N-nitrosourea (ENU)-mutagenized mouse strain. By contrast, a rare human TNFAIP3 allele encoding an A20 protein with 95% loss of phosphorylation, C243Y, caused spontaneous inflammatory disease in humans and mice. Analysis of the partial-phosphorylation A20 I325N allele in mice revealed diminished tolerance of bacterial lipopolysaccharide and poxvirus inoculation as tradeoffs for enhanced immunity.
Genome-wide identification of long noncoding RNAs in CD8+ T cells
Publisher: The American Association of Immunologists
Date: 15-06-2009
Abstract: Previous research into the molecular mechanisms that underlie Ag-specific CD8+ T cell differentiation and function has largely focused on the role of proteins. However, it is now apparent that the mammalian genome expresses large numbers of long (& nt) nonprotein-coding RNAs (ncRNAs), and there is increasing evidence that these RNAs have important regulatory functions, particularly in the regulation of epigenetic processes underpinning cell differentiation. In this study, we show that CD8+ T cells express hundreds of long ncRNAs, many of which are lymphoid-specific and/or change dynamically with lymphocyte differentiation or activation. Numerous ncRNAs surround or overlap immunologically important protein-coding genes and can be predicted to function via a range of regulatory mechanisms. The overlap of many long ncRNAs expressed in CD8+ T cells with microRNAs and small interfering RNAs further suggests that long ncRNAs may be processed into and exert their effects via smaller functional species. Finally, we show that the majority of long ncRNAs expressed in CD8+ T cells harbor signatures of evolutionary conservation, secondary structures, and/or regulated promoters, further supporting their functionality. Taken together, our findings represent the first systematic discovery of long ncRNAs expressed in CD8+ T cells and suggest that many of these transcripts are likely to play a role in adaptive immunity.
Supplementary Data from Lipid Uptake Is an Androgen-Enhanced Lipid Supply Pathway Associated with Prostate Cancer Disease Progression and Bone Metastasis
Publisher: American Association for Cancer Research (AACR)
Date: 03-04-2023
DOI: 10.1158/1541-7786.22513434.V1
Abstract: Supplementary Figures
Improved definition of the mouse transcriptome via targeted RNA sequencing
Publisher: Cold Spring Harbor Laboratory
Date: 05-2016
Abstract: Targeted RNA sequencing (CaptureSeq) uses oligonucleotide probes to capture RNAs for sequencing, providing enriched read coverage, accurate measurement of gene expression, and quantitative expression data. We applied CaptureSeq to refine transcript annotations in the current murine GRCm38 assembly. More than 23,000 regions corresponding to putative or annotated long noncoding RNAs (lncRNAs) and 154,281 known splicing junction sites were selected for targeted sequencing across five mouse tissues and three brain subregions. The results illustrate that the mouse transcriptome is considerably more complex than previously thought. We assemble more complete transcript isoforms than GENCODE, expand transcript boundaries, and connect interspersed islands of mapped reads. We describe a novel filtering pipeline that identifies previously unannotated but high-quality transcript isoforms. In this set, 911 GENCODE neighboring genes are condensed into 400 expanded gene models. Additionally, 594 GENCODE lncRNAs acquire an open reading frame (ORF) when their structure is extended with CaptureSeq. Finally, we validate our observations using current FANTOM and Mouse ENCODE resources.
Benchmarking of RNA-sequencing analysis workflows using whole-transcriptome RT-qPCR expression data
Publisher: Springer Science and Business Media LLC
Date: 08-05-2017
DOI: 10.1038/S41598-017-01617-3
Abstract: RNA-sequencing has become the gold standard for whole-transcriptome gene expression quantification. Multiple algorithms have been developed to derive gene counts from sequencing reads. While a number of benchmarking studies have been conducted, the question remains how in idual methods perform at accurately quantifying gene expression levels from RNA-sequencing reads. We performed an independent benchmarking study using RNA-sequencing data from the well established MAQCA and MAQCB reference s les. RNA-sequencing reads were processed using five workflows (Tophat-HTSeq, Tophat-Cufflinks, STAR-HTSeq, Kallisto and Salmon) and resulting gene expression measurements were compared to expression data generated by wet-lab validated qPCR assays for all protein coding genes. All methods showed high gene expression correlations with qPCR data. When comparing gene expression fold changes between MAQCA and MAQCB s les, about 85% of the genes showed consistent results between RNA-sequencing and qPCR data. Of note, each method revealed a small but specific gene set with inconsistent expression measurements. A significant proportion of these method-specific inconsistent genes were reproducibly identified in independent datasets. These genes were typically smaller, had fewer exons, and were lower expressed compared to genes with consistent expression measurements. We propose that careful validation is warranted when evaluating RNA-seq based expression profiles for this specific gene set.
Diagnostic Yield of Whole Genome Sequencing After Nondiagnostic Exome Sequencing or Gene Panel in Developmental and Epileptic Encephalopathies
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 30-03-2021
DOI: 10.1212/WNL.0000000000011655
Abstract: To assess the benefits and limitations of whole genome sequencing (WGS) compared to exome sequencing (ES) or multigene panel (MGP) in the molecular diagnosis of developmental and epileptic encephalopathies (DEE). We performed WGS of 30 comprehensively phenotyped DEE patient trios that were undiagnosed after first-tier testing, including chromosomal microarray and either research ES (n = 15) or diagnostic MGP (n = 15). Eight diagnoses were made in the 15 in iduals who received prior ES (53%): 3 in iduals had complex structural variants 5 had ES-detectable variants, which now had additional evidence for pathogenicity. Eleven diagnoses were made in the 15 MGP-negative in iduals (68%) the majority (n = 10) involved genes not included in the panel, particularly in in iduals with postneonatal onset of seizures and those with more complex presentations including movement disorders, dysmorphic features, or multiorgan involvement. A total of 42% of diagnoses were autosomal recessive or X-chromosome linked. WGS was able to improve diagnostic yield over ES primarily through the detection of complex structural variants (n = 3). The higher diagnostic yield was otherwise better attributed to the power of re-analysis rather than inherent advantages of the WGS platform. Additional research is required to assist in the assessment of pathogenicity of novel noncoding and complex structural variants and further improve diagnostic yield for patients with DEE and other neurogenetic disorders.
The Medical Genome Reference Bank contains whole genome and phenotype data of 2570 healthy elderly
Publisher: Springer Science and Business Media LLC
Date: 23-01-2020
DOI: 10.1038/S41467-019-14079-0
Abstract: Population health research is increasingly focused on the genetic determinants of healthy ageing, but there is no public resource of whole genome sequences and phenotype data from healthy elderly in iduals. Here we describe the first release of the Medical Genome Reference Bank (MGRB), comprising whole genome sequence and phenotype of 2570 elderly Australians depleted for cancer, cardiovascular disease, and dementia. We analyse the MGRB for single-nucleotide, indel and structural variation in the nuclear and mitochondrial genomes. MGRB in iduals have fewer disease-associated common and rare germline variants, relative to both cancer cases and the gnomAD and UK Biobank cohorts, consistent with risk depletion. Age-related somatic changes are correlated with grip strength in men, suggesting blood-derived whole genomes may also provide a biologic measure of age-related functional deterioration. The MGRB provides a broadly applicable reference cohort for clinical genetics and genomic association studies, and for understanding the genetics of healthy ageing.
Specific expression of long noncoding RNAs in the mouse brain
Publisher: Proceedings of the National Academy of Sciences
Date: 15-01-2008
Abstract: A major proportion of the mammalian transcriptome comprises long RNAs that have little or no protein-coding capacity (ncRNAs). Only a handful of such transcripts have been examined in detail, and it is unknown whether this class of transcript is generally functional or merely artifact. Using in situ hybridization data from the Allen Brain Atlas, we identified 849 ncRNAs (of 1,328 examined) that are expressed in the adult mouse brain and found that the majority were associated with specific neuroanatomical regions, cell types, or subcellular compartments. Examination of their genomic context revealed that the ncRNAs were expressed from erse places including intergenic, intronic, and imprinted loci and that many overlap with, or are transcribed antisense to, protein-coding genes of neurological importance. Comparisons between the expression profiles of ncRNAs and their associated protein-coding genes revealed complex relationships that, in combination with the specific expression profiles exhibited at both regional and subcellular levels, are inconsistent with the notion that they are transcriptional noise or artifacts of chromatin remodeling. Our results show that the majority of ncRNAs are expressed in the brain and provide strong evidence that the majority of processed transcripts with no protein-coding capacity function intrinsically as RNAs.
Long Noncoding RNAs CUPID1 and CUPID2 Mediate Breast Cancer Risk at 11q13 by Modulating the Response to DNA Damage
Publisher: Elsevier BV
Date: 08-2017
The long noncoding RNA MALAT1 promotes tumor-driven angiogenesis by up-regulating pro-angiogenic gene expression
Publisher: Impact Journals, LLC
Date: 02-02-2016
lncRNAdb: a reference database for long noncoding RNAs
Publisher: Oxford University Press (OUP)
Date: 25-11-2010
DOI: 10.1093/NAR/GKQ1138
A variant of the KLK4 gene is expressed as a cis sense-antisense chimeric transcript in prostate cancer cells
Publisher: Cold Spring Harbor Laboratory
Date: 20-04-2010
DOI: 10.1261/RNA.2019810
Abstract: In humans, more than 30,000 chimeric transcripts originating from 23,686 genes have been identified. The mechanisms and association of chimeric transcripts arising from chromosomal rearrangements with cancer are well established, but much remains unknown regarding the biogenesis and importance of other chimeric transcripts that arise from nongenomic alterations. Recently, a SLC45A3 – ELK4 chimera has been shown to be androgen-regulated, and is overexpressed in metastatic or high-grade prostate tumors relative to local prostate cancers. Here, we characterize the expression of a KLK4 cis sense–antisense chimeric transcript, and show other ex les in prostate cancer. Using non-protein-coding microarray analyses, we initially identified an androgen-regulated antisense transcript within the 3′ untranslated region of the KLK4 gene in LNCaP cells. The KLK4 cis -NAT was validated by strand-specific linker-mediated RT-PCR and Northern blotting. Characterization of the KLK4 cis -NAT by 5′ and 3′ rapid lification of cDNA ends (RACE) revealed that this transcript forms multiple fusions with the KLK4 sense transcript. Lack of KLK4 antisense promoter activity using reporter assays suggests that these transcripts are unlikely to arise from a trans -splicing mechanism. 5′ RACE and analyses of deep sequencing data from LNCaP cells treated ±androgens revealed six high-confidence sense–antisense chimeras of which three were supported by the cDNA databases. In this study, we have shown complex gene expression at the KLK4 locus that might be a hallmark of cis sense–antisense chimeric transcription.
NMNAT1 variants cause cone and cone-rod dystrophy
Publisher: Springer Science and Business Media LLC
Date: 28-11-2018
Human genomic DNA is widely interspersed with i-motif structures
Publisher: Cold Spring Harbor Laboratory
Date: 14-04-2022
DOI: 10.1101/2022.04.14.488274
Abstract: DNA i-motif structures are formed in the nucleus of human cells and are believed to provide critical genomic regulation. While the existence of i-motif structures in human cells has been demonstrated by immunofluorescent staining and by characterisation of select model genes, the abundance and distribution of such structures in the human genome has remained unclear. Here we utilize high affinity i-motif immunoprecipitation followed by sequencing to map i-motifs in human genomic DNA. Validated by biolayer interferometry and circular dichroism spectroscopy, our approach identified over 650,000 i-motif structures in human genomic DNA. The i-motif structures are widely distributed throughout the human genome and are common among highly expressed genes and in genes upregulated in G0/G1 cell cycle phase. Our findings provide experimental evidence for the widespread formation of i-motif structures in human genomic DNA.
Long noncoding RNAs and the genetics of cancer.
Publisher: Springer Science and Business Media LLC
Date: 09-05-2013
DOI: 10.1038/BJC.2013.233
mity: A highly sensitive mitochondrial variant analysis pipeline for whole genome sequencing data
Publisher: Cold Spring Harbor Laboratory
Date: 22-11-2019
DOI: 10.1101/852210
Abstract: Mitochondrial diseases (MDs) are the most common group of inherited metabolic disorders and are often challenging to diagnose due to extensive genotype-phenotype heterogeneity. MDs are caused by mutations in the nuclear or mitochondrial genome, where pathogenic mitochondrial variants are usually heteroplasmic and typically at much lower allelic fraction in the blood than affected tissues. Both genomes can now be readily analysed using unbiased whole genome sequencing (WGS), but most nuclear variant detection methods fail to detect low heteroplasmy variants in the mitochondrial genome. We present mity , a bioinformatics pipeline for detecting and interpreting heteroplasmic SNVs and INDELs in the mitochondrial genome using WGS data. In 2,980 healthy controls, we observed on average 3,166× coverage in the mitochondrial genome using WGS from blood. mity utilises this high depth to detect pathogenic mitochondrial variants, even at low heteroplasmy. mity enables easy interpretation of mitochondrial variants and can be incorporated into existing diagnostic WGS pipelines. This could simplify the diagnostic pathway, avoid invasive tissue biopsies and increase the diagnostic rate for MDs and other conditions caused by impaired mitochondrial function. mity is available from github.com/KCCG/mity under an MIT license. clare.puttick@crick.ac.uk , carolyn.sue@sydney.edu.au , MCowley@ccia.org.au
RNAcentral: a hub of information for non-coding RNA sequences
Publisher: Oxford University Press (OUP)
Date: 08-12-2018
DOI: 10.1093/NAR/GKY1206
Identification of archaeal genes encoding a novel stationary phase- response protein
Publisher: Elsevier BV
Date: 2000
DOI: 10.1016/S0167-4781(99)00216-X
Abstract: A novel stationary phase-response protein has been identified in the acid-soluble protein extract of the thermophilic archaeon, Thermococcus zilligii. N-Terminal sequencing data were used to identify likely genes for homologues of the protein in the complete genome sequences of various archaeal species. The corresponding genes were identified and analysed. The genes encode a protein ranging from 83 to 92 amino acids in length, with a calculated pI ranging from 4.6 to 9.7. The amino acid sequences of the genes were highly conserved, even between members belonging to the different archaeal kingdoms. The computed secondary structure of the protein indicates it consists of four large helical regions separated by short coiled regions. We propose this protein as a candidate regulator of gene expression in stationary phase.
Long noncoding RNAs in neuronal-glial fate specification and oligodendrocyte lineage maturation
Publisher: Springer Science and Business Media LLC
Date: 05-02-2010
Abstract: Long non-protein-coding RNAs (ncRNAs) are emerging as important regulators of cellular differentiation and are widely expressed in the brain. Here we show that many long ncRNAs exhibit dynamic expression patterns during neuronal and oligodendrocyte (OL) lineage specification, neuronal-glial fate transitions, and progressive stages of OL lineage elaboration including myelination. Consideration of the genomic context of these dynamically regulated ncRNAs showed they were part of complex transcriptional loci that encompass key neural developmental protein-coding genes, with which they exhibit concordant expression profiles as indicated by both microarray and in situ hybridization analyses. These included ncRNAs associated with differentiation-specific nuclear subdomains such as Gomafu and Neat1 , and ncRNAs associated with developmental enhancers and genes encoding important transcription factors and homeotic proteins. We also observed changes in ncRNA expression profiles in response to treatment with trichostatin A, a histone deacetylase inhibitor that prevents the progression of OL progenitors into post-mitotic OLs by altering lineage-specific gene expression programs. This is the first report of long ncRNA expression in neuronal and glial cell differentiation and of the modulation of ncRNA expression by modification of chromatin architecture. These observations explicitly link ncRNA dynamics to neural stem cell fate decisions, specification and epigenetic reprogramming and may have important implications for understanding and treating neuropsychiatric diseases.
Lipid uptake is an androgen-enhanced lipid supply pathway associated with prostate cancer disease progression and bone metastasis
Publisher: American Association for Cancer Research (AACR)
Date: 05-2019
DOI: 10.1158/1541-7786.MCR-18-1147
Abstract: Prostate cancer exhibits metabolic plasticity in acquiring lipids from uptake and lipogenesis at different disease stages, indicating potential therapeutic benefit by cotargeting lipid supply.
Initiating an undiagnosed diseases program in the Western Australian public health system
Publisher: Springer Science and Business Media LLC
Date: 03-05-2017
Protein-coding and non-coding gene expression analysis in differentiating human keratinocytes using a three-dimensional epidermal equivalent.
Publisher: Springer Science and Business Media LLC
Date: 25-05-2010
DOI: 10.1007/S00438-010-0543-6
Abstract: The epidermal compartment is complex and organized into several strata composed of keratinocytes (KCs), including basal, spinous, granular, and cornified layers. The continuous process of self-renewal and barrier formation is dependent on a homeostatic balance achieved amongst KCs involving proliferation, differentiation, and cell death. To determine genes responsible for initiating and maintaining a cornified epidermis, organotypic cultures comprised entirely of stratified KCs creating epidermal equivalents (EE) were raised from a submerged state to an air/liquid (A/L) interface. Compared to the array profile of submerged cultures containing KCs predominantly in a proliferative (relatively undifferentiated) state, EEs raised to an A/L interface displayed a remarkably consistent and distinct profile of mRNAs. Cultures lifted to an A/L interface triggered the induction of gene groups that regulate proliferation, differentiation, and cell death. Next, differentially expressed microRNAs (miRNAs) and long non-coding (lncRNA) RNAs were identified in EEs. Several differentially expressed miRNAs were validated by qRT-PCR and Northern blots. miRNAs 203, 205 and Let-7b were up-regulated at early time points (6, 18 and 24 h) but down-regulated by 120 h. To study the lncRNA regulation in EEs, we profiled lncRNA expression by microarray and validated the results by qRT-PCR. Although the differential expression of several lncRNAs is suggestive of a role in epidermal differentiation, their biological functions remain to be elucidated. The current studies lay the foundation for relevant model systems to address such fundamentally important biological aspects of epidermal structure and function in normal and diseased human skin.
Universal Alternative Splicing of Noncoding Exons
Publisher: Elsevier BV
Date: 02-2018
DOI: 10.1016/J.CELS.2017.12.005
Abstract: The human transcriptome is so large, erse, and dynamic that, even after a decade of investigation by RNA sequencing (RNA-seq), we have yet to resolve its true dimensions. RNA-seq suffers from an expression-dependent bias that impedes characterization of low-abundance transcripts. We performed targeted single-molecule and short-read RNA-seq to survey the transcriptional landscape of a single human chromosome (Hsa21) at unprecedented resolution. Our analysis reaches the lower limits of the transcriptome, identifying a fundamental distinction between protein-coding and noncoding gene content: almost every noncoding exon undergoes alternative splicing, producing a seemingly limitless variety of isoforms. Analysis of syntenic regions of the mouse genome shows that few noncoding exons are shared between human and mouse, yet human splicing profiles are recapitulated on Hsa21 in mouse cells, indicative of regulation by a deeply conserved splicing code. We propose that noncoding exons are functionally modular, with alternative splicing generating an enormous repertoire of potential regulatory RNAs and a rich transcriptional reservoir for gene evolution.
Cyclin E2 is the predominant E-cyclin associated with NPAT in breast cancer cells.
Publisher: Springer Science and Business Media LLC
Date: 19-02-2015
Somatic mutations in salivary duct carcinoma and potential therapeutic targets
Publisher: Impact Journals, LLC
Date: 25-05-2017
Improved diagnosis and care for rare diseases through implementation of precision public health framework
Publisher: Springer International Publishing
Date: 2017
DOI: 10.1007/978-3-319-67144-4_4
Abstract: Public health relies on technologies to produce and analyse data, as well as effectively develop and implement policies and practices. An ex le is the public health practice of epidemiology, which relies on computational technology to monitor the health status of populations, identify disadvantaged or at risk population groups and thereby inform health policy and priority setting. Critical to achieving health improvements for the underserved population of people living with rare diseases is early diagnosis and best care. In the rare diseases field, the vast majority of diseases are caused by destructive but previously difficult to identify protein-coding gene mutations. The reduction in cost of genetic testing and advances in the clinical use of genome sequencing, data science and imaging are converging to provide more precise understandings of the 'person-time-place' triad. That is: who is affected (people) when the disease is occurring (time) and where the disease is occurring (place). Consequently we are witnessing a paradigm shift in public health policy and practice towards 'precision public health'.Patient and stakeholder engagement has informed the need for a national public health policy framework for rare diseases. The engagement approach in different countries has produced highly comparable outcomes and objectives. Knowledge and experience sharing across the international rare diseases networks and partnerships has informed the development of the Western Australian Rare Diseases Strategic Framework 2015-2018 (RD Framework) and Australian government health briefings on the need for a National plan.The RD Framework is guiding the translation of genomic and other technologies into the Western Australian health system, leading to greater precision in diagnostic pathways and care, and is an ex le of how a precision public health framework can improve health outcomes for the rare diseases population.Five vignettes are used to illustrate how policy decisions provide the scaffolding for translation of new genomics knowledge, and catalyze transformative change in delivery of clinical services. The vignettes presented here are from an Australian perspective and are not intended to be comprehensive, but rather to provide insights into how a new and emerging 'precision public health' paradigm can improve the experiences of patients living with rare diseases, their caregivers and families.The conclusion is that genomic public health is informed by the in idual and family needs, and the population health imperatives of an early and accurate diagnosis which is the portal to best practice care. Knowledge sharing is critical for public health policy development and improving the lives of people living with rare diseases.
The eukaryotic genome as an RNA machine
Publisher: American Association for the Advancement of Science (AAAS)
Date: 28-03-2008
Abstract: The past few years have revealed that the genomes of all studied eukaryotes are almost entirely transcribed, generating an enormous number of non–protein-coding RNAs (ncRNAs). In parallel, it is increasingly evident that many of these RNAs have regulatory functions. Here, we highlight recent advances that illustrate the ersity of ncRNA control of genome dynamics, cell biology, and developmental programming.
Identification of OAF and PVRL1 as candidate genes for an ocular anomaly characterized by Peters anomaly type 2 and ectopia lentis
Publisher: Elsevier BV
Date: 03-2018
DOI: 10.1016/J.EXER.2017.12.012
Abstract: Keratolenticular dysgenesis (KLD) and ectopia lentis are congenital eye defects. The aim of this study is the identification of molecular genetic alterations responsible for those ocular anomalies with neurologic impairment in an in idual with a de novo balanced chromosome translocation t(11 )(q23.3 q11.2)dn. Disruption of OAF, the human orthologue of the Drosophila oaf, by the 11q23.3 breakpoint results in reduced expression of this transcriptional regulator. Furthermore, four most likely nonfunctional chimeric transcripts comprising up to OAF exon 3, derived from the der(11) allele, have also been identified. This locus has been implicated by publicly available genome-wide association data in corneal disease and corneal topography. The expression of the poliovirus receptor-related 1(PVRL1) or nectin cell adhesion molecule 1 (NECTIN1), a paralogue of nectin cell adhesion molecule 3 (PVRL3) associated with congenital ocular defects, situated 500 kb upstream from 11q23.3 breakpoint, is increased. The 18q11.2 breakpoint is localized between cutaneous T-cell lymphoma-associated antigen 1(CTAGE1) and retinoblastoma binding protein 8 (RBBP8) genes. Genomic imbalance that could contribute to the observed phenotype was excluded. Analysis of gene expression datasets throughout normal murine ocular lens embryogenesis suggests that OAF expression is significantly enriched in the lens from early stages of development through adulthood, whereas PVRL1 is lens-enriched until E12.5 and then down-regulated. This contrasts with the observation that the proposita's lymphoblastoid cell lines exhibit low OAF and high PVRL1 expression as compared to control, which offers further support that the alterations described above are most likely responsible for the clinical phenotype. Finally, gene interaction topology data for PVRL1 also agree with our proposal that disruption of OAF by the translocation breakpoint and misregulation of PVRL1 due to a position effect contribute to the observed ocular and neurological phenotype.
Genome sequencing as a first-line genetic test in familial dilated cardiomyopathy
Publisher: Elsevier BV
Date: 03-2019
Computational Approaches for Functional Prediction and Characterisation of Long Noncoding RNAs
Publisher: Elsevier BV
Date: 10-2016
DOI: 10.1016/J.TIG.2016.08.004
Abstract: Although a considerable portion of eukaryotic genomes is transcribed as long noncoding RNAs (lncRNAs), the vast majority are functionally uncharacterised. The rapidly expanding catalogue of mechanistically investigated lncRNAs has provided evidence for distinct functional subclasses, which are now ripe for exploitation as a general model to predict functions for uncharacterised lncRNAs. By utilising publicly-available genome-wide datasets and computational methods, we present several developed and emerging in silico approaches to characterise and predict the functions of lncRNAs. We propose that the application of these techniques provides valuable functional and mechanistic insight into lncRNAs, and is a crucial step for informing subsequent functional studies.
Preparing Australia for Genomic Medicine: Data, Computing and Digital Health
Publisher: AMPCo
Date: 30-03-2019
DOI: 10.5694/MJA2.50032
Endometriosis risk alleles at 1p36.12 act through inverse regulation of CDC42 and LINC00339
Publisher: Oxford University Press (OUP)
Date: 20-09-2016
DOI: 10.1093/HMG/DDW320
Abstract: Genome-wide association studies (GWAS) have identified markers within the WNT4 region on chromosome 1p36.12 showing consistent and strong association with increasing endometriosis risk. Fine mapping using sequence and imputed genotype data has revealed strong candidates for the causal SNPs within these critical regions however, the molecular pathogenesis of these SNPs is currently unknown. We used gene expression data collected from whole blood from 862 in iduals and endometrial tissue from 136 in iduals from independent populations of European descent to examine the mechanism underlying endometriosis susceptibility. Association mapping results from 7,090 in iduals (2,594 cases and 4,496 controls) supported rs3820282 as the SNP with the strongest association for endometriosis risk (P = 1.84 × 10−5, OR = 1.244 (1.126-1.375)). SNP rs3820282 is a significant eQTL in whole blood decreasing expression of LINC00339 (also known as HSPC157) and increasing expression of CDC42 (P = 2.0 ×10−54 and 4.5x10−4 respectively). The largest effects were for two LINC00339 probes (P = 2.0 ×10−54 1.0 × 10−34). The eQTL for LINC00339 was also observed in endometrial tissue (P = 2.4 ×10−8) with the same direction of effect for both whole blood and endometrial tissue. There was no evidence for eQTL effects for WNT4. Chromatin conformation capture provides evidence for risk SNPs interacting with the promoters of both LINC00339 and CDC4 and luciferase reporter assays suggest the risk SNP rs12038474 is located in a transcriptional silencer for CDC42 and the risk allele increases expression of CDC42. However, no effect of rs3820282 was observed in the LINC00339 expression in Ishikawa cells. Taken together, our results suggest that SNPs increasing endometriosis risk in this region act through CDC42, but further functional studies are required to rule out inverse regulation of both LINC00339 and CDC42.
Targeted sequencing for gene discovery and quantification using RNA CaptureSeq
Publisher: Springer Science and Business Media LLC
Date: 04-04-2014
Abstract: RNA sequencing (RNAseq) s les the majority of expressed genes infrequently, owing to the large size, complex splicing and wide dynamic range of eukaryotic transcriptomes. This results in sparse sequencing coverage that can hinder robust isoform assembly and quantification. RNA capture sequencing (CaptureSeq) addresses this challenge by using oligonucleotide probes to capture selected genes or regions of interest for targeted sequencing. Targeted RNAseq provides enhanced coverage for sensitive gene discovery, robust transcript assembly and accurate gene quantification. Here we describe a detailed protocol for all stages of RNA CaptureSeq, from initial probe design considerations and capture of targeted genes to final assembly and quantification of captured transcripts. Initial probe design and final analysis can take less than 1 d, whereas the central experimental capture stage requires ∼7 d.
RNAcentral: a comprehensive database of non-coding RNA sequences
Publisher: Oxford University Press (OUP)
Date: 28-10-2016
DOI: 10.1093/NAR/GKW1008
Attitudes of Australian health professionals towards rapid genomic testing in neonatal and paediatric intensive care
Publisher: Springer Science and Business Media LLC
Date: 31-05-2019
Integrating exome sequencing into a diagnostic pathway for epileptic encephalopathy: Evidence of clinical utility and cost effectiveness
Publisher: Wiley
Date: 17-06-2216
DOI: 10.1002/MGG3.355
Asparagine Synthetase Deficiency causes reduced proliferation of cells under conditions of limited asparagine
Publisher: Elsevier BV
Date: 11-2015
DOI: 10.1016/J.YMGME.2015.08.007
Abstract: Asparagine Synthetase Deficiency is a recently described cause of profound intellectual disability, marked progressive cerebral atrophy and variable seizure disorder. To date there has been limited functional data explaining the underlying pathophysiology. We report a new case with compound heterozygous mutations in the ASNS gene (NM_183356.3:c. [866G>C] [1010C>T]). Both variants alter evolutionarily conserved amino acids and were predicted to be pathogenic based on in silico protein modelling that suggests disruption of the critical ATP binding site of the ASNS enzyme. In patient fibroblasts, ASNS expression as well as protein and mRNA stability are not affected by these variants. However, there is markedly reduced proliferation of patient fibroblasts when cultured in asparagine-limited growth medium, compared to parental and wild type fibroblasts. Restricting asparagine replicates the physiology within the blood-brain-barrier, with limited transfer of dietary derived asparagine, resulting in reliance of neuronal cells on intracellular asparagine synthesis by the ASNS enzyme. These functional studies offer insight into the underlying pathophysiology of the dramatic progressive cerebral atrophy associated with Asparagine Synthetase Deficiency.
Index suffix–prefix overlaps by (w, k)-minimizer to generate long contigs for reads compression
Publisher: Oxford University Press (OUP)
Date: 08-11-2018
DOI: 10.1093/BIOINFORMATICS/BTY936
Abstract: Advanced high-throughput sequencing technologies have produced massive amount of reads data, and algorithms have been specially designed to contract the size of these datasets for efficient storage and transmission. Reordering reads with regard to their positions in de novo assembled contigs or in explicit reference sequences has been proven to be one of the most effective reads compression approach. As there is usually no good prior knowledge about the reference sequence, current focus is on the novel construction of de novo assembled contigs. We introduce a new de novo compression algorithm named minicom. This algorithm uses large k-minimizers to index the reads and subgroup those that have the same minimizer. Within each subgroup, a contig is constructed. Then some pairs of the contigs derived from the subgroups are merged into longer contigs according to a (w, k)-minimizer-indexed suffix–prefix overlap similarity between two contigs. This merging process is repeated after the longer contigs are formed until no pair of contigs can be merged. We compare the performance of minicom with two reference-based methods and four de novo methods on 18 datasets (13 RNA-seq datasets and 5 whole genome sequencing datasets). In the compression of single-end reads, minicom obtained the smallest file size for 22 of 34 cases with significant improvement. In the compression of paired-end reads, minicom achieved 20–80% compression gain over the best state-of-the-art algorithm. Our method also achieved a 10% size reduction of compressed files in comparison with the best algorithm under the reads-order preserving mode. These excellent performances are mainly attributed to the exploit of the redundancy of the repetitive substrings in the long contigs. uansliu/minicom Supplementary data are available at Bioinformatics online.
Whole exome and genome sequencing in mendelian disorders
Publisher: Springer Science and Business Media LLC
Date: 15-08-2022
DOI: 10.1038/S41431-022-01162-2
Abstract: Whole genome sequencing (WGS) improves Mendelian disorder diagnosis over whole exome sequencing (WES) however, additional diagnostic yields and costs remain undefined. We investigated differences between diagnostic and cost outcomes of WGS and WES in a cohort with suspected Mendelian disorders. WGS was performed in 38 WES-negative families derived from a 64 family Mendelian cohort that previously underwent WES. For new WGS diagnoses, contemporary WES reanalysis determined whether variants were diagnosable by original WES or unique to WGS. Diagnostic rates were estimated for WES and WGS to simulate outcomes if both had been applied to the 64 families. Diagnostic costs were calculated for various genomic testing scenarios. WGS diagnosed 34% (13/38) of WES-negative families. However, contemporary WES reanalysis on average 2 years later would have diagnosed 18% (7/38 families) resulting in a WGS-specific diagnostic yield of 19% (6/31 remaining families). In WES-negative families, the incremental cost per additional diagnosis using WGS following WES reanalysis was AU$36,710 (£19,407 US$23,727) and WGS alone was AU$41,916 (£22,159 US$27,093) compared to WES-reanalysis. When we simulated the use of WGS alone as an initial genomic test, the incremental cost for each additional diagnosis was AU$29,708 (£15,705 US$19,201) whereas contemporary WES followed by WGS was AU$36,710 (£19,407 US$23,727) compared to contemporary WES. Our findings confirm that WGS is the optimal genomic test choice for maximal diagnosis in Mendelian disorders. However, accepting a small reduction in diagnostic yield, WES with subsequent reanalysis confers the lowest costs. Whether WES or WGS is utilised will depend on clinical scenario and local resourcing and availability.
The histone demethylase JMJD1A induces cell migration and invasion by up-regulating the expression of the long noncoding RNA MALAT1
Publisher: Impact Journals, LLC
Date: 18-02-2014
Machine learning annotation of human branchpoints.
Publisher: Oxford University Press (OUP)
Date: 28-10-2017
DOI: 10.1093/BIOINFORMATICS/BTX688
Abstract: The branchpoint element is required for the first lariat-forming reaction in splicing. However current catalogues of human branchpoints remain incomplete due to the difficulty in experimentally identifying these splicing elements. To address this limitation, we have developed a machine-learning algorithm—branchpointer—to identify branchpoint elements solely from gene annotations and genomic sequence. Using branchpointer, we annotate branchpoint elements in 85% of human gene introns with sensitivity (61.8%) and specificity (97.8%). In addition to annotation, branchpointer can evaluate the impact of SNPs on branchpoint architecture to inform functional interpretation of genetic variants. Branchpointer identifies all published deleterious branchpoint mutations annotated in clinical variant databases, and finds thousands of additional clinical and common genetic variants with similar predicted effects. This genome-wide annotation of branchpoints provides a reference for the genetic analysis of splicing, and the interpretation of noncoding variation. Branchpointer is written and implemented in the statistical programming language R and is freely available under a BSD license as a package through Bioconductor. Supplementary data are available at Bioinformatics online.
The Medical Genome Reference Bank: a whole-genome data resource of 4000 healthy elderly individuals. Rationale and cohort design
Publisher: Springer Science and Business Media LLC
Date: 24-10-2019
Genomics and personalised whole-of-life healthcare
Publisher: Elsevier BV
Date: 09-2014
DOI: 10.1016/J.MOLMED.2014.04.001
Abstract: Genome sequencing has the potential for stratified cancer treatment and improved diagnostics for rare disorders. However, sequencing needs to be utilised in risk stratification on a population scale to deepen the impact on the health system by addressing common diseases, where in idual genomic variants have variable penetrance and minor impact. As the accuracy of genomic risk predictors is bounded by heritability, environmental factors such as diet, lifestyle, and microbiome have to be considered. Large-scale, longitudinal research programmes need to study the intrinsic properties between both genetics and environment to unravel their risk contribution. During this discovery process, frameworks need to be established to counteract unrealistic expectations. Sufficient scientific evidence is needed to interpret sources of uncertainty and inform decision making for clinical management and personal health.
Supplemental Files from Lipid Uptake Is an Androgen-Enhanced Lipid Supply Pathway Associated with Prostate Cancer Disease Progression and Bone Metastasis
Publisher: American Association for Cancer Research (AACR)
Date: 03-04-2023
DOI: 10.1158/1541-7786.22513437.V1
Abstract: Figure S1: LNCaP, VCaP and DuCaP cells were grown in charcoal-dextran stripped serum (CSS) for 48 h and treated with increasing concentrations of R1881 or DHT in the presence or absence of Enzalutamide (10 µM) or vehicle (Ctrl) for 48 h. Figure S2: Androgens increased lipid uptake of long-chain fatty acids. LAPC4 cells were grown in CSS for 48 h and treated with 1 nM R1881 or vehicle for 48 h. Figure S3: (A) LNCaP cells were synchronized in G0/G1 by androgen deprivation (CSS for 48 h) followed by treatment with Tunicamycin (1 mg/mL), Hydroxyurea (1 M), or Nocodazole (25 ug/mL) for another 24 h, placing cell cycle blocks in G0/G1, S phase and mitosis, respectively. Figure S4: Oncomine analysis of candidate lipid transporters in (A) Grasso [2], (B) Varambally [3] and (C) LaTulippe datasets [4] comparing gene expression of normal prostate gland versus localized, primary prostate cancer tumor s les. Figure S5: (A) DuCaP (top panel) and VCaP cells (bottom panel) were grown in CSS for 48 h and treated with 10 nM DHT in the absence or presence of Enz (10 µM) or vehicle (Ctrl) for 48 h. Table S1. Primer sequences
Expression of distinct RNAs from 3′ untranslated regions
Publisher: Oxford University Press (OUP)
Date: 12-11-2010
DOI: 10.1093/NAR/GKQ1158
Widespread promoter methylation of synaptic plasticity genes in long-term potentiation in the adult brain in vivo.
Publisher: Springer Science and Business Media LLC
Date: 23-03-2017
Whole-exome sequencing reanalysis at 12 months boosts diagnosis and is cost-effective when applied early in Mendelian disorders
Publisher: Elsevier BV
Date: 12-2018
DOI: 10.1038/GIM.2018.39
Abstract: Whole-exome sequencing (WES) has revolutionized Mendelian diagnostics, however, there is no consensus on the timing of data review in undiagnosed in iduals and only preliminary data on the cost-effectiveness of this technology. We aimed to assess the utility of WES data reanalysis for diagnosis in Mendelian disorders and to analyze the cost-effectiveness of this technology compared with a traditional diagnostic pathway. WES was applied to a cohort of 54 patients from 37 families with a variety of Mendelian disorders to identify the genetic etiology. Reanalysis was performed after 12 months with an improved WES diagnostic pipeline. A comparison was made between costs of a modeled WES pathway and a traditional diagnostic pathway in a cohort with intellectual disability (ID). Reanalysis of WES data at 12 months improved diagnostic success from 30 to 41% due to interim publication of disease genes, expanded phenotype data from referrer, and an improved bioinformatics pipeline. Cost analysis on the ID cohort showed average cost savings of US$586 (AU$782) for each additional diagnosis. Early application of WES in Mendelian disorders is cost-effective and reanalysis of an undiagnosed in idual at a 12-month time point increases total diagnoses by 11%.
Identification of a dinucleotide signature that discriminates coding from non-coding long RNAs
Publisher: Frontiers Media SA
Date: 09-09-2014
A De Novo Mutation in the Sodium-Activated Potassium Channel KCNT2 Alters Ion Selectivity and Causes Epileptic Encephalopathy
Publisher: Elsevier BV
Date: 10-2017
Realizing the significance of noncoding functionality in clinical genomics
Publisher: Springer Science and Business Media LLC
Date: 08-2018
Regulated post-transcriptional RNA cleavage diversifies the eukaryotic transcriptome
Publisher: Cold Spring Harbor Laboratory
Date: 02-11-2010
Abstract: The complexity of the eukaryotic transcriptome is generated by the interplay of transcription initiation, termination, alternative splicing, and other forms of post-transcriptional modification. It was recently shown that RNA transcripts may also undergo cleavage and secondary 5′ capping. Here, we show that post-transcriptional cleavage of RNA contributes to the ersification of the transcriptome by generating a range of small RNAs and long coding and noncoding RNAs. Using genome-wide histone modification and RNA polymerase II occupancy data, we confirm that the vast majority of intraexonic CAGE tags are derived from post-transcriptional processing. By comparing exonic CAGE tags to tissue-matched PARE data, we show that the cleavage and subsequent secondary capping is regulated in a developmental-stage- and tissue-specific manner. Furthermore, we find evidence of prevalent RNA cleavage in numerous transcriptomic data sets, including SAGE, cDNA, small RNA libraries, and deep-sequenced size-fractionated pools of RNA. These cleavage products include mRNA variants that retain the potential to be translated into shortened functional protein isoforms. We conclude that post-transcriptional RNA cleavage is a key mechanism that expands the functional repertoire and scope for regulatory control of the eukaryotic transcriptome.
Intergenic disease-associated regions are abundant in novel transcripts
Publisher: Springer Science and Business Media LLC
Date: 12-2017
MEN ε/β nuclear-retained non-coding RNAs are up-regulated upon muscle differentiation and are essential components of paraspeckles
Publisher: Cold Spring Harbor Laboratory
Date: 22-12-2008
Abstract: Studies of the transcriptional output of the human and mouse genomes have revealed that there are many more transcripts produced than can be accounted for by predicted protein-coding genes. Using a custom microarray, we have identified 184 non-coding RNAs that exhibit more than twofold up- or down-regulation upon differentiation of C2C12 myoblasts into myotubes. Here, we focus on the Men ε/β locus, which is up-regulated 3.3-fold during differentiation. Two non-coding RNA isoforms are produced from a single RNA polymerase II promoter, differing in the location of their 3′ ends. Men ε is a 3.2-kb polyadenylated RNA, whereas Men β is an ∼20-kb transcript containing a genomically encoded poly(A)-rich tract at its 3′-end. The 3′-end of Men β is generated by RNase P cleavage. The Men ε/β transcripts are localized to nuclear paraspeckles and directly interact with NONO. Knockdown of MEN ε/β expression results in the disruption of nuclear paraspeckles. Furthermore, the formation of paraspeckles, after release from transcriptional inhibition by DRB treatment, was suppressed in MEN ε/β -depleted cells. Our findings indicate that the MEN ε/β non-coding RNAs are essential structural/organizational components of paraspeckles.
Regulated Expression of PTPRJ/CD148 and an Antisense Long Noncoding RNA in Macrophages by Proinflammatory Stimuli
Publisher: Public Library of Science (PLoS)
Date: 28-06-2013
NRED: A database of long noncoding RNA expression
Publisher: Oxford University Press (OUP)
Date: 10-2009
DOI: 10.1093/NAR/GKN617
SNORD-host RNA Zfas1 is a regulator of mammary development and a potential marker for breast cancer.
Publisher: Cold Spring Harbor Laboratory
Date: 04-2011
DOI: 10.1261/RNA.2528811
Abstract: Long noncoding RNAs (lncRNAs) are increasingly recognized to play major regulatory roles in development and disease. To identify novel regulators in breast biology, we identified differentially regulated lncRNAs during mouse mammary development. Among the highest and most differentially expressed was a transcript ( Zfas1 ) antisense to the 5′ end of the protein-coding gene Znfx1 . In vivo, Zfas1 RNA is localized within the ducts and alveoli of the mammary gland. Zfas1 intronically hosts three previously undescribed C/D box snoRNAs (SNORDs): Snord12 , Snord12b , and Snord12c . In contrast to the general assumption that noncoding SNORD-host transcripts function only as vehicles to generate snoRNAs, knockdown of Zfas1 in a mammary epithelial cell line resulted in increased cellular proliferation and differentiation, while not substantially altering the levels of the SNORDs. In support of an independent function, we also found that Zfas1 is extremely stable, with a half-life h. Expression analysis of the SNORDs revealed these were expressed at different levels, likely a result of distinct structures conferring differential stability. While there is relatively low primary sequence conservation between Zfas1 and its syntenic human ortholog ZFAS1 , their predicted secondary structures have similar features. Like Zfas1 , ZFAS1 is highly expressed in the mammary gland and is down-regulated in breast tumors compared to normal tissue. We propose a functional role for Zfas1/ ZFAS1 in the regulation of alveolar development and epithelial cell differentiation in the mammary gland, which, together with its dysregulation in human breast cancer, suggests ZFAS1 as a putative tumor suppressor gene.
Expanding the spectrum of PEX16 mutations and novel insights into disease mechanisms.
Publisher: Elsevier BV
Date: 09-2018
Noncoding RNAs in long-term memory formation
Publisher: SAGE Publications
Date: 16-11-2008
Abstract: Current research exploring the molecular basis of memory focuses mainly on proteins despite recent genomic studies reporting the abundant transcription of non-protein-coding RNA (ncRNA). Although ncRNAs are involved in a erse range of biological processes, they are particularly prevalent within the nervous system, where they contribute towards the complexity and function of the mammalian brain. In this review, we apply recent advances in ncRNA biology to predict a critical role for ncRNAs in the molecular mechanisms underlying memory formation and maintenance. We describe the role of ncRNAs in regulating the translation, stability, and editing of mRNA populations in response to synaptic activity during memory formation and the role of ncRNAs in the epigenetic and transcriptional programs that underlie long-term memory storage. We also consider ncRNAs acting as an additional avenue of communication between neurons by their intercellular trafficking. Taken together, the emerging evidence suggests a central role for ncRNAs in memory formation and provokes novel research directions in this field. NEUROSCIENTIST 14(5):434—445, 2008. DOI: 10.1177/1073858408319187
The Human Mitochondrial Transcriptome
Publisher: Elsevier BV
Date: 08-2011
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