ORCID Profile
0000-0002-7038-5079
Current Organisations
Centenary Institute
,
University of Sydney
,
University of New South Wales
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Cellular nervous system | Cell neurochemistry | Neurosciences
Publisher: Elsevier BV
Date: 08-2011
DOI: 10.1016/J.CCR.2011.07.003
Abstract: Constitutional epimutations of tumor suppressor genes manifest as promoter methylation and transcriptional silencing of a single allele in normal somatic tissues, thereby predisposing to cancer. Constitutional MLH1 epimutations occur in in iduals with young-onset cancer and demonstrate non-Mendelian inheritance through their reversal in the germline. We report a cancer-affected family showing dominant transmission of soma-wide highly mosaic MLH1 methylation and transcriptional repression linked to a particular genetic haplotype. The epimutation was erased in spermatozoa but reinstated in the somatic cells of the next generation. The affected haplotype harbored two single nucleotide substitutions in tandem c.-27C > A located near the transcription initiation site and c.85G > T. The c.-27C > A variant significantly reduced transcriptional activity in reporter assays and is the probable cause of this epimutation.
Publisher: Springer Science and Business Media LLC
Date: 19-05-2023
DOI: 10.1007/S00018-023-04799-4
Abstract: Virilizer-like m 6 A methyltransferase-associated protein (VIRMA) maintains the stability of the m 6 A writer complex. Although VIRMA is critical for RNA m 6 A deposition, the impact of aberrant VIRMA expression in human diseases remains unclear. We show that VIRMA is lified and overexpressed in 15–20% of breast cancers. Of the two known VIRMA isoforms, the nuclear-enriched full-length but not the cytoplasmic-localised N-terminal VIRMA promotes m 6 A-dependent breast tumourigenesis in vitro and in vivo. Mechanistically, we reveal that VIRMA overexpression upregulates the m 6 A-modified long non-coding RNA, NEAT1 , which contributes to breast cancer cell growth. We also show that VIRMA overexpression enriches m 6 A on transcripts that regulate the unfolded protein response (UPR) pathway but does not promote their translation to activate the UPR under optimal growth conditions. Under stressful conditions that are often present in tumour microenvironments, VIRMA-overexpressing cells display enhanced UPR and increased susceptibility to death. Our study identifies oncogenic VIRMA overexpression as a vulnerability that may be exploited for cancer therapy.
Publisher: American Society for Clinical Investigation
Date: 22-06-2021
Publisher: Wiley
Date: 27-11-2016
Abstract: Until recently, retention of introns in mature mRNAs has been regarded as a consequence of mis-splicing. Intron-retaining transcripts are thought to be non-functional because they are readily degraded by nonsense-mediated decay. However, recent advances in next-generation sequencing technologies have enabled the detection of numerous transcripts that retain introns. As we review herein, intron-retaining mRNAs play an essential conserved role in normal physiology and an emergent role in erse diseases. Intron retention should no longer be overlooked as a key mechanism that independently reduces gene expression in normal biology. Exploring its contribution to the development and/or maintenance of diseases is of increasing importance.
Publisher: Wiley
Date: 12-12-2021
DOI: 10.1111/IMM.13435
Abstract: Monocytes play a crucial role in maintaining homeostasis and mediating a successful innate immune response. They also act as central players in erse pathological conditions, thus making them an attractive therapeutic target. Within the bone marrow, monocytes arise from a committed precursor termed Common Monocyte Progenitor (cMoP). However, molecular mechanisms that regulate the differentiation of cMoP to various monocytic subsets remain unclear. Herein, we purified murine myeloid precursors for deep poly‐A‐enriched RNA sequencing to understand the role of alternative splicing in the development and differentiation of monocytes under homeostasis. Our analyses revealed intron retention to be the major alternative splicing mechanism involved in the monocyte differentiation cascade, especially in the differentiation of Ly6C hi monocytes to Ly6C lo monocytes. Furthermore, we found that the intron retention of key genes involved in the differentiation of murine Ly6C hi to Ly6C lo monocytes was also conserved in humans. Our data highlight the unique role of intron retention in the regulation of the monocytic differentiation pathway.
Publisher: MDPI AG
Date: 11-12-2020
Abstract: Vast transcriptomics and epigenomics changes are characteristic of human cancers, including leukaemia. At remission, we assume that these changes normalise so that omics-profiles resemble those of healthy in iduals. However, an in-depth transcriptomic and epigenomic analysis of cancer remission has not been undertaken. A striking exemplar of targeted remission induction occurs in chronic myeloid leukaemia (CML) following tyrosine kinase inhibitor (TKI) therapy. Using RNA sequencing and whole-genome bisulfite sequencing, we profiled s les from chronic-phase CML patients at diagnosis and remission and compared these to healthy donors. Remarkably, our analyses revealed that abnormal splicing distinguishes remission s les from normal controls. This phenomenon is independent of the TKI drug used and in striking contrast to the normalisation of gene expression and DNA methylation patterns. Most remarkable are the high intron retention (IR) levels that even exceed those observed in the diagnosis s les. Increased IR affects cell cycle regulators at diagnosis and splicing regulators at remission. We show that aberrant splicing in CML is associated with reduced expression of specific splicing factors, histone modifications and reduced DNA methylation. Our results provide novel insights into the changing transcriptomic and epigenomic landscapes of CML patients during remission. The conceptually unanticipated observation of widespread aberrant alternative splicing after remission induction warrants further exploration. These results have broad implications for studying CML relapse and treating minimal residual disease.
Publisher: Elsevier BV
Date: 03-2011
DOI: 10.1038/MODPATHOL.2010.212
Abstract: Epigenetic silencing of cancer-related genes by promoter methylation is a frequent event in sporadic colorectal cancer. The CpG island methylator phenotype (CIMP+), in which discrete genes throughout the genome are simultaneously methylated, and long-range epigenetic silencing, whereby multiple genes within contiguous chromosomal regions are methylated, have been described in subsets of colorectal cancer. We previously reported the concurrent methylation of the mismatch repair gene MLH1 with a cluster of flanking genes in chromosome region 3p22 in sporadic colorectal carcinoma exhibiting microsatellite instability and the BRAF V600E mutation. Herein, we aimed to determine whether methylation of MLH1 and neighbouring 3p22 genes, singly or concomitantly, correlate with the germline c.-93G>A SNP within the MLH1 promoter, CIMP+ and other clinicopathological and molecular features of the tumours. By studying a cohort of 946 sporadic colorectal cancer cases, we show a strong association between concordant methylation of ≥ 3 of five 3p22 genes with CIMP+ and the BRAF V600E mutation (P<0.001). These associations were independent of microsatellite instability, as concomitant methylation of 3p22 genes other than MLH1 was found in microsatellite stable cancers. These findings show that long-range epigenetic silencing across 3p22 occurs in the context of CIMP+ and the BRAF V600E mutation, and only gives rise to microsatellite instability when this process encompasses MLH1. Furthermore, the strong relationship between long-range epigenetic silencing of 3p22 and CIMP+ provides further evidence that these two purportedly distinct epigenetic phenotypes represent a single entity with a common aetiology. Low-level methylation of MLH1 and flanking 3p22 genes, as well as the BRAF V600E mutation, were detected in the apparently normal colonic mucosa of a small number of cases whose tumours showed a similar molecular profile, suggesting that these concurring genetic and epigenetic events can occur as a field defect in neoplastic development.
Publisher: Springer Science and Business Media LLC
Date: 02-02-2017
Publisher: Cold Spring Harbor Laboratory
Date: 18-05-2009
DOI: 10.1101/732537
Abstract: Mouse kidney parvovirus (MKPV) is a member of the provisional Chapparvovirus genus that causes renal disease in immune-compromised mice, with a disease course reminiscent of polyomavirus-associated nephropathy in immune-suppressed kidney transplant patients. Here we map four MKPV transcripts, created by alternative splicing, to a common transcription initiation region, and use mass spectrometry to identify “p10” and “p15” as novel chapparvovirus accessory proteins produced in MKPV-infected kidneys. p15 and a splicing-dependent putative accessory protein NS2 are conserved in all near-complete tetrapod chapparvovirus genomes currently available (from mammals, birds and a reptile). In contrast, p10 may be encoded only by viruses with % amino acid identity to MKPV. We show that MKPV is kidney-tropic and that the bat chapparvovirus DrPV-1 and a non-human primate chapparvovirus, CKPV, are also found in the kidneys of their hosts. We propose, therefore, that chapparvoviruses with % VP1 amino acid identity to MKPV be classified into a genus dubbed Nephroparvovirus , which is consistent with nomenclature for the genus Erythroparvovirus .
Publisher: MDPI AG
Date: 23-09-2021
Abstract: Vascular smooth muscle cells (VSMCs) display extraordinary phenotypic plasticity. This allows them to differentiate or dedifferentiate, depending on environmental cues. The ability to ‘switch’ between a quiescent contractile phenotype to a highly proliferative synthetic state renders VSMCs as primary mediators of vascular repair and remodelling. When their plasticity is pathological, it can lead to cardiovascular diseases such as atherosclerosis and restenosis. Coinciding with significant technological and conceptual innovations in RNA biology, there has been a growing focus on the role of alternative splicing in VSMC gene expression regulation. Herein, we review how alternative splicing and its regulatory factors are involved in generating protein ersity and altering gene expression levels in VSMC plasticity. Moreover, we explore how recent advancements in the development of splicing-modulating therapies may be applied to VSMC-related pathologies.
Publisher: Oxford University Press (OUP)
Date: 25-05-2020
DOI: 10.1093/NAR/GKAA435
Abstract: Monocytes and macrophages are essential components of the innate immune system. Herein, we report that intron retention (IR) plays an important role in the development and function of these cells. Using Illumina mRNA sequencing, Nanopore direct cDNA sequencing and proteomics analysis, we identify IR events that affect the expression of key genes roteins involved in macrophage development and function. We demonstrate that decreased IR in nuclear-detained mRNA is coupled with increased expression of genes encoding regulators of macrophage transcription, phagocytosis and inflammatory signalling, including ID2, IRF7, ENG and LAT. We further show that this dynamic IR program persists during the polarisation of resting macrophages into activated macrophages. In the presence of proinflammatory stimuli, intron-retaining CXCL2 and NFKBIZ transcripts are rapidly spliced, enabling timely expression of these key inflammatory regulators by macrophages. Our study provides novel insights into the molecular factors controlling vital regulators of the innate immune response.
Publisher: BMJ
Date: 2007
Publisher: Springer Science and Business Media LLC
Date: 08-05-2018
DOI: 10.1038/S41598-018-24203-7
Abstract: Myelopoiesis involves differentiation of hematopoietic stem cells to cellular populations that are restricted in their self-renewal capacity, beginning with the common myeloid progenitor (CMP) and leading to mature cells including monocytes and granulocytes. This complex process is regulated by various extracellular and intracellular signals including microRNAs (miRNAs). We characterised the miRNA profile of human CD34 + CD38 + myeloid progenitor cells, and mature monocytes and granulocytes isolated from cord blood using TaqMan Low Density Arrays. We identified 19 miRNAs that increased in both cell types relative to the CMP and 27 that decreased. miR-125b and miR-10a were decreased by 10-fold and 100-fold respectively in the mature cells. Using in vitro granulopoietic differentiation of human CD34 + cells we show that decreases in both miR-125b and miR-10a correlate with a loss of CD34 expression and gain of CD11b and CD15 expression. Candidate target mRNAs were identified by co-incident predictions between the miRanda algorithm and genes with increased expression during differentiation. Using luciferase assays we confirmed MCL1 and FUT4 as targets of miR-125b and the transcription factor KLF4 as a target of miR-10a. Together, our data identify miRNAs with differential expression during myeloid development and reveal some relevant miRNA-target pairs that may contribute to physiological differentiation.
Publisher: Wiley
Date: 18-10-2014
DOI: 10.1111/CAS.12532
Publisher: Cold Spring Harbor Laboratory
Date: 06-07-2022
DOI: 10.1101/2022.07.05.498887
Abstract: Despite an abundance of publicly available RNA sequencing datasets, a lack of integrated user-friendly tools hinder exploration of alternative splicing. SpliceWiz is an innovative, ultra-fast graphical R application that accurately quantifies splicing events using isoform-specific alignments. It is designed to accommodate hundreds of s les typically seen in clinical datasets. Novel event filters remove low-confidence measurements from analysis, enhancing accuracy over existing methods. Group-averaged strand-specific sequencing coverage plots enable clear visualization of group differences in alternative splicing, using a new file format with demonstrable performance improvements over the current BigWig standard. ompBAM , a C++ library upon which SpliceWiz is built, automates multi-threaded alignment file processing for R package developers. SpliceWiz is a powerful platform for erse users to explore alternative splicing in large datasets.
Publisher: Frontiers Media SA
Date: 28-02-2020
Publisher: Public Library of Science (PLoS)
Date: 23-01-2020
Publisher: Springer Science and Business Media LLC
Date: 14-07-2023
Publisher: Springer Science and Business Media LLC
Date: 17-02-2017
Publisher: Informa UK Limited
Date: 20-08-2021
Publisher: Frontiers Media SA
Date: 03-05-2017
Publisher: Life Science Alliance, LLC
Date: 11-05-2022
Abstract: Pathogenic mycobacteria inhibit inflammasome activation to establish infection. Although it is known that potassium efflux is a trigger for inflammasome activation, the interaction between mycobacterial infection, potassium efflux, and inflammasome activation has not been investigated. Here, we use Mycobacterium marinum infection of zebrafish embryos and Mycobacterium tuberculosis infection of THP-1 cells to demonstrate that pathogenic mycobacteria up-regulate the host WNK signalling pathway kinases SPAK and OXSR1 which control intracellular potassium balance. We show that genetic depletion or inhibition of OXSR1 decreases bacterial burden and intracellular potassium levels. The protective effects of OXSR1 depletion are at least partially mediated by NLRP3 inflammasome activation, caspase-mediated release of IL-1β, and downstream activation of protective TNF-α. The elucidation of this druggable pathway to potentiate inflammasome activation provides a new avenue for the development of host-directed therapies against intracellular infections.
Publisher: American Society of Hematology
Date: 28-04-2016
DOI: 10.1182/BLOOD-2016-01-692764
Abstract: Dynamic intron retention programs exist in the murine megakaryocyte and erythroid and human erythroid lineages. Intron retention inversely correlates with expression levels of a large set of transcripts.
Publisher: Springer Science and Business Media LLC
Date: 28-05-2018
Publisher: Cold Spring Harbor Laboratory
Date: 04-11-2022
DOI: 10.1101/2022.11.03.514952
Abstract: RNA modifications are essential for the establishment of cellular identity. Although increasing evidence indicates that RNA modifications regulate the innate immune response, their role in monocyte-to-macrophage differentiation and polarisation is unclear. To date, most studies have focused on m 6 A, while other RNA modifications, including 5hmC, remain poorly characterised. The interplay between different RNA modifications that may occur in specific cellular contexts remains similarly unexplored. We profiled m 6 A and 5hmC epitranscriptomes, transcriptomes, translatomes and proteomes of monocytes and macrophages at rest and pro- and anti-inflammatory states. We observed that decreased expression of m 6 A and 5hmC writers, METTL3 and TET-enzymes respectively, facilitated monocyte-to-macrophage differentiation. Despite a global trend of m 6 A and 5hmC loss during macrophage differentiation, enrichment of m 6 A and/or 5hmC on specific categories of transcripts essential for macrophage differentiation positively correlated with their expression and translation. m 6 A and 5hmC mark and are associated with the expression of transcripts with critical functions in pro- and anti-inflammatory macrophages. Notably, we also discovered the coexistence of m 6 A and 5hmC marking alternatively-spliced isoforms and/or opposing ends of the untranslated regions (UTR) of transcripts with key roles in macrophage biology. In specific ex les, RNA 5hmC controls the decay of transcripts independently of m 6 A. This study: i) uncovers m 6 A, 5hmC and their writer enzymes as regulators of monocyte and macrophage gene expression programs and ii) provides a comprehensive dataset to interrogate the role of RNA modifications in a plastic system. Altogether, this work sheds light on the role of RNA modifications as central regulators of effector cells in innate immunity.
Publisher: Oxford University Press (OUP)
Date: 28-01-2016
DOI: 10.1093/NAR/GKW041
Publisher: Elsevier BV
Date: 05-2023
Publisher: Springer Science and Business Media LLC
Date: 30-01-2018
DOI: 10.1038/S41375-018-0021-4
Abstract: Alternative splicing expands the transcriptome thereby promoting protein ersity. It governs critical cellular processes such as differentiation, proliferation and apoptosis in a tissue-specific manner. Aberrant splicing consequent to mutations in splicing factors and disruption of isoform ratios in key regulatory genes provides an important contribution to the pathogenesis of the myelodysplastic syndromes and myeloid leukemia. We review here the central role of alternative splicing in regulating myelopoiesis, and provide clear ex les of how global splicing disruption or specific aberrant splicing events might promote leukemogenesis. We discuss the growing number of mechanistic links between epigenetic factors and alternative splicing. Finally, we address the potential utility of alternatively spliced isoforms as biomarkers and the development of novel therapies that modulate alternative splicing in myeloid and other malignancies.
Publisher: Springer Science and Business Media LLC
Date: 02-10-2020
DOI: 10.1038/S41467-020-18729-6
Abstract: Tet-enzyme-mediated 5-hydroxymethylation of cytosines in DNA plays a crucial role in mouse embryonic stem cells (ESCs). In RNA also, 5-hydroxymethylcytosine (5hmC) has recently been evidenced, but its physiological roles are still largely unknown. Here we show the contribution and function of this mark in mouse ESCs and differentiating embryoid bodies. Transcriptome-wide mapping in ESCs reveals hundreds of messenger RNAs marked by 5hmC at sites characterized by a defined unique consensus sequence and particular features. During differentiation a large number of transcripts, including many encoding key pluripotency-related factors (such as Eed and Jarid2), show decreased cytosine hydroxymethylation. Using Tet-knockout ESCs, we find Tet enzymes to be partly responsible for deposition of 5hmC in mRNA. A transcriptome-wide search further reveals mRNA targets to which Tet1 and Tet2 bind, at sites showing a topology similar to that of 5hmC sites. Tet-mediated RNA hydroxymethylation is found to reduce the stability of crucial pluripotency-promoting transcripts. We propose that RNA cytosine 5-hydroxymethylation by Tets is a mark of transcriptome flexibility, inextricably linked to the balance between pluripotency and lineage commitment.
Publisher: Springer Science and Business Media LLC
Date: 16-11-2017
Publisher: Springer Science and Business Media LLC
Date: 11-07-2010
DOI: 10.1038/NSMB.1841
Abstract: We have recently shown that transcription initiation RNAs (tiRNAs) are derived from sequences immediately downstream of transcription start sites. Here, using cytoplasmic and nuclear small RNA high-throughput sequencing datasets, we report the identification of a second class of nuclear-specific approximately 17- to 18-nucleotide small RNAs whose 3' ends map precisely to the splice donor site of internal exons in animals. These splice-site RNAs (spliRNAs) are associated with highly expressed genes and show evidence of developmental stage- and region-specific expression. We also show that tiRNAs are localized to the nucleus, are enriched at chromatin marks associated with transcription initiation and possess a 3'-nucleotide bias. Additionally, we find that microRNA-offset RNAs (moRNAs), the miR-15/16 cluster previously linked to oncosuppression and most small nucleolar RNA (snoRNA)-derived small RNAs (sdRNAs) are enriched in the nucleus, whereas most miRNAs and two H/ACA sdRNAs are cytoplasmically enriched. We propose that nuclear-localized tiny RNAs are involved in the epigenetic regulation of gene expression.
Publisher: China Anti-cancer Association
Date: 2018
Publisher: Wiley
Date: 07-04-2015
DOI: 10.1002/PATH.4518
Publisher: Springer Science and Business Media LLC
Date: 10-12-2014
DOI: 10.1038/NCOMMS6522
Abstract: MicroRNAs (miRNAs) are critical to somatic cell reprogramming into induced pluripotent stem cells (iPSCs), however, exactly how miRNA expression changes support the transition to pluripotency requires further investigation. Here we use a murine secondary reprogramming system to s le cellular trajectories towards iPSCs or a novel pluripotent 'F-class' state and perform small RNA sequencing. We detect sweeping changes in an early and a late wave, revealing that distinct miRNA milieus characterize alternate states of pluripotency. miRNA isoform expression is common but surprisingly varies little between cell states. Referencing other omic data sets generated in parallel, we find that miRNA expression is changed through transcriptional and post-transcriptional mechanisms. miRNA transcription is commonly regulated by dynamic histone modification, while DNA methylation/demethylation consolidates these changes at multiple loci. Importantly, our results suggest that a novel subset of distinctly expressed miRNAs supports pluripotency in the F-class state, substituting for miRNAs that serve such roles in iPSCs.
Publisher: Cold Spring Harbor Laboratory
Date: 25-07-2021
DOI: 10.1101/2021.07.24.453629
Abstract: During ontogeny, macrophages develop from CD115 + precursors, including erythro-myeloid progenitors (EMP). EMP arise in the embryonic yolk sac, the primary site of early haematopoiesis. In adults, CD115 + bone marrow-derived monocytes represent essential macrophage precursors. Herein, we identify a CD115 - macrophage precursor within the adult bone marrow that is unrelated to the classical monocyte lineage but rather shares transcriptomic and functional characteristics of embryonic EMP. These EMPROR (for E rythro M yeloid Pr ecurs or ) cells are capable of efficiently generating macrophages in disease settings. During early development, EMPROR cells were largely absent from the yolk sac but were instead found at the embryonic-maternal interface in the uterine wall. Unexpectedly, the latter site contains robust haematopoietic activity and harbours defined embryonic haematopoietic progenitor cells, including classical CD115 + EMP. Our data suggest the existence of an alternative pathway of macrophage generation in the adult. Further, we uncover a hitherto unknown site of earliest blood cell development.
Publisher: Springer Science and Business Media LLC
Date: 05-01-2017
Publisher: Oxford University Press (OUP)
Date: 10-11-2022
DOI: 10.1093/NAR/GKAC994
Abstract: Dynamic intron retention (IR) in vertebrate cells is of widespread biological importance. Aberrant IR is associated with numerous human diseases including several cancers. Despite consistent reports demonstrating that intrinsic sequence features can help introns evade splicing, conflicting findings about cell type- or condition-specific IR regulation by trans-regulatory and epigenetic mechanisms demand an unbiased and systematic analysis of IR in a controlled experimental setting. We integrated matched mRNA sequencing (mRNA-Seq), whole-genome bisulfite sequencing (WGBS), nucleosome occupancy methylome sequencing (NOMe-Seq) and chromatin immunoprecipitation sequencing (ChIP-Seq) data from primary human myeloid and lymphoid cells. Using these multi-omics data and machine learning, we trained two complementary models to determine the role of epigenetic factors in the regulation of IR in cells of the innate immune system. We show that increased chromatin accessibility, as revealed by nucleosome-free regions, contributes substantially to the retention of introns in a cell-specific manner. We also confirm that intrinsic characteristics of introns are key for them to evade splicing. This study suggests an important role for chromatin architecture in IR regulation. With an increasing appreciation that pathogenic alterations are linked to RNA processing, our findings may provide useful insights for the development of novel therapeutic approaches that target aberrant splicing.
Publisher: Future Medicine Ltd
Date: 2019
Abstract: Aim: To determine whether epigenetic modifications of DNA regulate gene expression and alternative splicing during terminal granulopoiesis. Materials & methods: Using whole genome bisulfite sequencing, reduced representation hydroxymethylation profiling and mRNA sequencing, we compare changes in DNA methylation, DNA hydroxymethylation, gene expression and alternative splicing in mouse promyelocytes and granulocytes. Results & conclusion: We show reduced DNA methylation at the promoters and enhancers of key granulopoiesis genes, indicating a regulatory role in the activation of lineage-specific genes during differentiation. Notably, increased DNA hydroxymethylation in exons is associated with preferential inclusion of specific exons in granulocytes. Overall, DNA methylation and hydroxymethylation changes at particular genomic loci may play specific roles in gene regulation or alternative splicing during terminal granulopoiesis. Data deposition: Whole genome bisulfite sequencing of mouse promyelocytes and granulocytes: Gene Expression Omnibus (GSE85517) mRNA sequencing of mouse promyelocytes and granulocytes: Gene Expression Omnibus (GSE48307) reduced representation 5-hydroxymethylation profiling of mouse promyelocytes and granulocytes: Bioproject (PRJNA495696).
Publisher: Elsevier BV
Date: 10-2018
Publisher: Wiley
Date: 09-12-2022
DOI: 10.1111/ACEL.13755
Abstract: The aged brain is associated with an inevitable decline in cognitive function and increased vulnerability to neurodegenerative disorders. Multiple molecular hallmarks have been associated with the aging nervous system through transcriptomics and proteomic studies. Recently, epitranscriptomic analysis has highlighted the role of RNA chemical modification in various biological processes. In particular, N 6‐methyladenosine (m6A), the most abundant internal modification in eukaryotic mRNAs, has been functionally linked to multiple aspects of RNA metabolism with the roles of m6A in processes such as learning and memory, leading to our current investigation of how the m6A‐transcriptomic landscape is shaped during aging. Using the inbred C57BL/6 line, we compared the m6A‐transcriptomic profiles from the hippoc i of young (3‐month‐old) and aged (20‐month‐old) mice. Methylated RNA immunoprecipitation (MeRIP)‐sequencing analysis revealed hyper‐ and hypomethylation in 426 and 102 genes, respectively, in the aged hippoc us (fold change .5, false discovery rate .05). By correlating the methylation changes to their steady‐state transcript levels in the RNA‐Seq data, we found a significant concordance between m6A and transcript levels in both directions. Notably, the myelin regulator gene Gpr17 was downregulated in the aged hippoc us concomitant with reduced m6A levels in its 3'UTR. Using reporter constructs and mutagenesis analysis, we demonstrated that the putative m6A sites in the 3'UTR of Gpr17 are important for mRNA translation but not for regulating transcript stability. Overall, the positive correlation between m6A and the transcript expression levels indicates a co‐transcriptional regulation of m6A with gene expression changes that occur in the aged mouse hippoc us.
Publisher: Elsevier BV
Date: 04-2022
DOI: 10.1016/J.TIG.2021.11.005
Abstract: N6-methyladenosine or m
Publisher: Springer Science and Business Media LLC
Date: 08-05-2017
DOI: 10.1038/NCOMMS15134
Abstract: While intron retention (IR) is considered a widely conserved and distinct mechanism of gene expression control, its regulation is poorly understood. Here we show that DNA methylation directly regulates IR. We also find reduced occupancy of MeCP2 near the splice junctions of retained introns, mirroring the reduced DNA methylation at these sites. Accordingly, MeCP2 depletion in tissues and cells enhances IR. By analysing the MeCP2 interactome using mass spectrometry and RNA co-precipitation, we demonstrate that decreased MeCP2 binding near splice junctions facilitates IR via reduced recruitment of splicing factors, including Tra2b, and increased RNA polymerase II stalling. These results suggest an association between IR and a slower rate of transcription elongation, which reflects inefficient splicing factor recruitment. In summary, our results reinforce the interdependency between alternative splicing involving IR and epigenetic controls of gene expression.
Publisher: BMJ
Date: 04-2006
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 04-2021
DOI: 10.1161/STROKEAHA.120.031523
Abstract: Cerebral cavernous malformation (CCM) is a common cerebrovascular disease. CCMs are major causes of stroke, cerebral hemorrhage, and neurological deficits in young in iduals. Loss-of-function mutations in CCM1 , CCM2 , and CCM3 have been identified to cause CCM in humans. Ccm2-like ( Ccm2l ) is a paralog of Ccm2 and is predominantly expressed in endothelial cells (ECs). CCM2L (CCM2-like) competes with CCM2 for binding to CCM1 and has been shown to have an antagonistic function to that of CCM2 during vascular development. The role of CCM2L in CCM pathogenesis is unknown. We isolated brain ECs from the inducible-CCM mouse models for gene expression analysis. Micro-computed tomography imaging was used to analyze CCM lesion burden from the genetic cross of Ccm2l knockout mice ( Ccm2l −/− ) with Ccm1 or Ccm2 -deficient mice to determine the role of Ccm2l in CCM pathogenesis. Genetic crosses with Map3k3 fl/fl mice were used to determine the role of Map3k3 in Ccm2l -facilitated CCM formation. We demonstrated increased Ccm2l expression in brain ECs of Ccm2 -deficient mice. Analysis of RNA-seq data from CCM patient s les revealed a trend of increased CCM2L expression and its positive correlation with Kruppel-like factor 2/4 (KLF2/4 ) expression. Micro-computed tomography revealed that the deletion of Ccm2l in Ccm2 -deficient mice increased CCM lesion volume compared with that of controls but had no effect on lesion numbers. Correlating to the increased lesion burden, Klf2/4 mRNA expressions in brain ECs were significantly increased in double knockouts ( Ccm2 - and Ccm2l -deficient mice) compared with that of controls ( Ccm2 deficient). Hemizygous deletion of Map3k3 in ECs relieved CCM lesion burden in the double knockouts. These results suggest that CCM2L regulates the Map3k3-KLF signaling pathway in CCM pathogenesis. Loss of CCM2L aggravates CCM lesion formation in the Ccm2 -deficient mouse model through increased Map3k3-KLF signaling. Our data suggest that increased Ccm2l expression is a compensatory mechanism in CCM pathogenesis.
Publisher: Springer Science and Business Media LLC
Date: 15-03-2017
Publisher: Elsevier BV
Date: 03-2018
DOI: 10.1016/J.SEMCDB.2017.07.030
Abstract: RNA sequencing has revealed a striking ersity in transcriptomic complexity, to which alternative splicing is a major contributor. Intron retention (IR) is a conserved form of alternative splicing that was originally overlooked in normal mammalian physiology and development, due mostly to difficulties in its detection. IR has recently been revealed as an independent mechanism of controlling and enhancing the complexity of gene expression. IR facilitates rapid responses to biological stimuli, is involved in disease pathogenesis, and can generate novel protein isoforms. Many challenges, however, remain in detecting and quantifying retained introns and in determining their effects on cellular phenotype. In this review, we provide an overview of these challenges, and highlight approaches that can be used to address them.
Publisher: Elsevier BV
Date: 12-2009
DOI: 10.1038/MODPATHOL.2009.130
Abstract: O(6)-methylguanine DNA methyltransferase (MGMT) is a DNA repair protein that restores mutagenic O(6)-methylguanine to guanine. MGMT methylation is frequently observed in sporadic colorectal cancer and was recently correlated with the C>T allele at SNP rs16906252, within the transcriptional enhancer element of the promoter. MGMT methylation has also been associated with KRAS mutations, particularly G>A transitions. We studied 1123 colorectal carcinoma to define the molecular and clinicopathological profiles associated with MGMT methylation. Furthermore, we assessed factors contributing to MGMT methylation in the development of colorectal cancer by studying the allelic pattern of MGMT methylation using SNP rs16906252, and the methylation status of neighbouring genes within 10q26 in selected tumours and matched normal colonic mucosa. MGMT methylation was detected by combined bisulphite restriction analysis in 28% of tumours and was associated with a number of characteristics, including CDKN2A methylation, absent lymphovascular space invasion and KRAS mutations (but not specifically with KRAS G>A transitions). In a multivariate analysis adjusted for age and sex, MGMT methylation was associated with the T allele of SNP rs16906252 (P T SNP. We show that the T allele at SNP rs16906252 is a key determinant in the onset of MGMT methylation in colorectal cancer, whereas the association of methylation at MGMT and CDKN2A suggests that these loci may be targets of a common mechanism of epigenetic dysregulation.
Publisher: American Association for the Advancement of Science (AAAS)
Date: 28-01-2022
Abstract: DNA methyltransferases (DNMTs) catalyze DNA methylation, and their functions in mammalian embryonic development and diseases including cancer have been extensively studied. However, regulation of DNMTs remains under study. Here, we show that CCAAT/enhancer binding protein α (CEBPA) interacts with the long splice isoform DNMT3A, but not the short isoform DNMT3A2. CEBPA, by interacting with DNMT3A N-terminus, blocks DNMT3A from accessing DNA substrate and thereby inhibits its activity. Recurrent tumor-associated CEBPA mutations, such as preleukemic CEBPA N321D mutation, which is particularly potent in causing AML with high mortality, disrupt DNMT3A association and cause aberrant DNA methylation, notably hypermethylation of PRC2 target genes. Consequently, leukemia cells with the CEBPA N321D mutation are hypersensitive to hypomethylation agents. Our results provide insights into the functional difference between DNMT3A isoforms and the regulation of de novo DNA methylation at specific loci in the genome. Our study also suggests a therapeutic strategy for the treatment of CEBPA -mutated leukemia with DNA-hypomethylating agents.
Publisher: MDPI AG
Date: 06-06-2013
Abstract: One of the major characteristics of HIV-1 is its high genetic variability and extensive heterogeneity. This characteristic is due to its molecular traits, which in turn allows it to vary, recombine, and ersify at a high frequency. As such, it generates complex molecular forms, termed recombinants, which evade the human immune system and so survive. There is no sequence constraint to the recombination pattern as it appears to occur at inter-group (between groups M and O), as well as inter- and intra-subtype within group M. Rapid emergence and active global transmission of HIV-1 recombinants, known as circulating recombinant forms (CRFs) and unique recombinant forms (URFs), requires urgent attention. To date, 55 CRFs have been reported around the world. The first CRF01_AE originated from Central Africa but spread widely in Asia. The most recent CRF CRF55_01B is a recombinant form of CRF01_AE and subtype B, although its origin is yet to be publicly disclosed. HIV-1 recombination is an ongoing event and plays an indispensable role in HIV epidemics in different regions. Africa, Asia and South America are identified as recombination hot-spots. They are affected by continual emergence and co-circulation of newly emerging CRFs and URFs, which are now responsible for almost 20% of HIV-1 infections worldwide. Better understanding of recombinants is necessary to determine their biological and molecular attributes.
Publisher: Massachusetts Medical Society
Date: 15-02-2007
DOI: 10.1056/NEJMOA064522
Publisher: Elsevier BV
Date: 05-2022
DOI: 10.1016/J.SEMCDB.2021.05.023
Abstract: Activity-dependent gene expression and protein translation underlie the ability of neurons to dynamically adjust their synaptic strength in response to sensory experience and during learning. The emerging field of epitranscriptomics (RNA modifications) has rapidly shifted our views on the mechanisms that regulate gene expression. Among hundreds of biochemical modifications on RNA, N
Publisher: Wiley
Date: 20-07-2018
DOI: 10.1111/IMCB.12186
Abstract: Conventional dendritic cells (cDCs) are continuously replenished by bone marrow-derived precursors called pre-DCs, which traffic through the blood to peripheral tissues. Pre-DCs are a heterogeneous population that includes cDC subset-committed progenitors, namely pre-cDC1 and pre-cDC2, which give rise to mature cDC1 and cDC2, respectively. Regulation of pre-DC subset trafficking is thought to aid the host response to immune challenge. However, the molecular cues regulating pre-cDC1 versus pre-cDC2 trafficking toward peripheral sites during homeostasis and disease remain elusive. Here, we report that pre-cDC1 but not pre-cDC2 express the T helper type 1-associated chemokine receptor CXCR3. Moreover, we identify a cell-intrinsic role for CXCR3 in the trafficking of pre-cDC1 to melanoma tumors but not to non-inflamed organs. We also show that tumor cDC1 numbers can be increased pharmacologically by targeting dipeptidyl peptidase-4 (CD26), a negative regulator of CXCR3 ligands. Our findings demonstrate that pre-cDC1 trafficking is regulated distinctly from pre-cDC2, which is relevant for our understanding of the DC lineage in the context of cancer and inflammation.
Publisher: Wiley
Date: 16-05-2013
DOI: 10.1111/BJH.12364
Abstract: MicroRNAs (miRNAs) are key to the pathogenesis of human malignancies and increasingly recognized as potential biomarkers and therapeutic targets. Haematological malignancies, being the earliest human malignancies linked to aberrant miRNA expression, have consistently underpinned our understanding of the role that miRNAs play in cancer development. Here, we review the expanding roles attributed to miRNAs in the pathogenesis of different types of myeloid malignancies and highlight key findings.
Publisher: Elsevier BV
Date: 08-2013
DOI: 10.1016/J.CELL.2013.06.052
Abstract: Intron retention (IR) is widely recognized as a consequence of mis-splicing that leads to failed excision of intronic sequences from pre-messenger RNAs. Our bioinformatic analyses of transcriptomic and proteomic data of normal white blood cell differentiation reveal IR as a physiological mechanism of gene expression control. IR regulates the expression of 86 functionally related genes, including those that determine the nuclear shape that is unique to granulocytes. Retention of introns in specific genes is associated with downregulation of splicing factors and higher GC content. IR, conserved between human and mouse, led to reduced mRNA and protein levels by triggering the nonsense-mediated decay (NMD) pathway. In contrast to the prevalent view that NMD is limited to mRNAs encoding aberrant proteins, our data establish that IR coupled with NMD is a conserved mechanism in normal granulopoiesis. Physiological IR may provide an energetically favorable level of dynamic gene expression control prior to sustained gene translation.
Start Date: 11-2023
End Date: 11-2026
Amount: $475,659.00
Funder: Australian Research Council
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