ORCID Profile
0000-0001-5806-4662
Current Organisations
University of Valencia, School of Psychology
,
Ministry of Education and Science
,
James Cook University
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Publisher: Royal Society of Chemistry (RSC)
Date: 2015
DOI: 10.1039/C5MB00245A
Abstract: The article describes a novel method (CRCmiRTar) for a CRC-specific prediction of functional miRNA-target interactions based on a machine learning approach.
Publisher: Springer New York
Date: 2013
Publisher: Elsevier
Date: 2021
Publisher: Impact Journals, LLC
Date: 26-12-2015
Abstract: The present study identified miR-638 as one of the most significantly overexpressed miRNAs in metastatic lesions of melanomas compared with primary melanomas. miR-638 enhanced the tumorigenic properties of melanoma cells in vitro and lung colonization in vivo. mRNA expression profiling identified new candidate genes including TP53INP2 as miR-638 targets, the majority of which are involved in p53 signalling. Overexpression of TP53INP2 severely attenuated proliferative and invasive capacity of melanoma cells which was reversed by miR-638. Depletion of miR-638 stimulated expression of p53 and p53 downstream target genes and induced apoptosis and autophagy. miR-638 promoter analysis identified the miR-638 target transcription factor associated protein 2α (TFAP2A/AP-2α) as a direct negative regulator of miR-638, suggestive for a double-negative regulatory feedback loop. Taken together, miR-638 supports melanoma progression and suppresses p53-mediated apoptosis pathways, autophagy and expression of the transcriptional repressor TFAP2A/AP-2α.
Publisher: Springer Science and Business Media LLC
Date: 20-03-2017
DOI: 10.1038/ONC.2017.25
Publisher: Wiley
Date: 31-05-2012
Publisher: Springer Science and Business Media LLC
Date: 30-07-2013
DOI: 10.1038/ONC.2012.324
Abstract: WEE1 kinase has been described as a major gate keeper at the G2 cell cycle checkpoint and to be involved in tumour progression in different malignant tumours. Here we analysed the expression levels of WEE1 in a series of melanoma patient s les and melanoma cell lines using immunoblotting, quantitative real-time PCR and immunohistochemistry. WEE1 expression was significantly downregulated in patient s les of metastatic origin as compared with primary melanomas and in melanoma cell lines of high aggressiveness as compared with cell lines of low aggressiveness. Moreover, there was an inverse correlation between the expression of WEE1 and WEE1-targeting microRNA miR-195. Further analyses showed that transfection of melanoma cell lines with miR-195 indeed reduced WEE1 mRNA and protein expression in these cells. Reporter gene analysis confirmed direct targeting of the WEE1 3' untranslated region (3'UTR) by miR-195. Overexpression of miR-195 in SK-Mel-28 melanoma cells was accompanied by WEE1 reduction and significantly reduced stress-induced G2-M cell cycle arrest, which could be restored by stable overexpression of WEE1. Moreover, miR-195 overexpression and WEE1 knockdown, respectively, increased melanoma cell proliferation. miR-195 overexpression also enhanced migration and invasiveness of melanoma cells. Taken together, the present study shows that WEE1 expression in malignant melanoma is directly regulated by miR-195. miR-195-mediated downregulation of WEE1 in metastatic lesions may help to overcome cell cycle arrest under stress conditions in the local tissue microenvironment to allow unrestricted growth of tumour cells.
Publisher: Springer Netherlands
Date: 2013
Publisher: Oxford University Press (OUP)
Date: 28-06-2021
DOI: 10.1093/NAR/GKAB520
Abstract: Three decades of research have established the CCCTC-binding factor (CTCF) as a ubiquitously expressed chromatin organizing factor and master regulator of gene expression. A new role for CTCF as a regulator of alternative splicing (AS) has now emerged. CTCF has been directly and indirectly linked to the modulation of AS at the in idual transcript and at the transcriptome-wide level. The emerging role of CTCF-mediated regulation of AS involves erse mechanisms including transcriptional elongation, DNA methylation, chromatin architecture, histone modifications, and regulation of splicing factor expression and assembly. CTCF thereby appears to not only co-ordinate gene expression regulation but contributes to the modulation of transcriptomic complexity. In this review, we highlight previous discoveries regarding the role of CTCF in AS. In addition, we summarize detailed mechanisms by which CTCF mediates AS regulation. We propose opportunities for further research designed to examine the possible fate of CTCF-mediated alternatively spliced genes and associated biological consequences. CTCF has been widely acknowledged as the ‘master weaver of the genome’. Given its multiple connections, further characterization of CTCF’s emerging role in splicing regulation might extend its functional repertoire towards a ‘conductor of the splicing orchestra’.
Publisher: Oxford University Press (OUP)
Date: 13-07-2012
DOI: 10.1093/NAR/GKS657
Publisher: Royal Society of Chemistry (RSC)
Date: 2012
DOI: 10.1039/C2MB05277F
Abstract: Cell adhesion in the normal colon is typically associated with differentiated cells, whereas in cancerous colon it is associated with advanced tumors. For advanced tumors growing evidence supports the existence of stem-like cells that have originated from transdifferentiation. Because stem cells can also be transformed in their own niche, at the base of the Lieberkühn's crypts, we conjectured that cell adhesion can also be critical in early tumorigenesis. To assess this hypothesis we built an annotated, multi-valued logic model addressing cell adhesion of normal and tumorigenic stem cells in the human colon. The model accounts for (i) events involving intercellular adhesion structures, (ii) interactions involving cytoskeleton-related structures, (iii) compartmental distribution of α/β/γ/δ-catenins, and (iv) variations in critical cell adhesion regulators (e.g., ILK, FAK, IQGAP, SNAIL, Caveolin). We developed a method that can deal with graded multiple inhibitions, something which is not possible with conventional logical approaches. The model comprises 315 species (including 26 genes), interconnected by 269 reactions. Simulations of the model covered six scenarios, which considered two types of colonic cells (stem vs. differentiated cells), under three conditions (normal, stressed and tumor). Each condition results from the combination of 92 inputs. We compared our multi-valued logic approach with the conventional Boolean approach for one specific ex le and validated the predictions against published data. Our analysis suggests that stem cells in their niche synthesize high levels of cytoplasmatic E-cadherin and CdhEP(Ser684,686,692), even under normal-mitogenic stimulus or tumorigenic conditions. Under these conditions, E-cadherin would be incorporated into the plasmatic membrane, but only as a non-adhesive CdhE_β-catenin_IQGAP complex. Under stress conditions, however, this complex could be displaced, yielding adhesive CdhE_β-catenin((cis/trans)) complexes. In the three scenarios tested with stem cells, desmosomes or tight junctions were not assembled. Other model predictions include expected levels of the nuclear complex β-catenin_TCF4 and the anti-apoptotic protein Survivin for both normal and tumorigenic colonic stem cells.
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: Oxford University Press (OUP)
Date: 16-12-2022
DOI: 10.1093/BIB/BBAC519
Abstract: Extensive investigation of gene fusions in cancer has led to the discovery of novel biomarkers and therapeutic targets. To date, most studies have neglected chromosomal rearrangement-independent fusion transcripts and complex fusion structures such as double or triple-hop fusions, and fusion-circRNAs. In this review, we untangle fusion-related terminology and propose a classification system involving both gene and transcript fusions. We highlight the importance of RNA-level fusions and how long-read sequencing approaches can improve detection and characterization. Moreover, we discuss novel bioinformatic tools to identify fusions in long-read sequencing data and strategies to experimentally validate and functionally characterize fusion transcripts.
Publisher: Springer New York
Date: 2013
Publisher: Springer Science and Business Media LLC
Date: 29-12-2022
DOI: 10.1186/S13058-022-01593-1
Abstract: After many years of neglect in the field of alternative splicing, the importance of intron retention (IR) in cancer has come into focus following landmark discoveries of aberrant IR patterns in cancer. Many solid and liquid tumours are associated with drastic increases in IR, and such patterns have been pursued as both biomarkers and therapeutic targets. Paradoxically, breast cancer (BrCa) is the only tumour type in which IR is reduced compared to adjacent normal breast tissue. In this study, we have conducted a pan-cancer analysis of IR with emphasis on BrCa and its subtypes. We explored mechanisms that could cause aberrant and pathological IR and clarified why normal breast tissue has unusually high IR. Strikingly, we found that aberrantly decreasing IR in BrCa can be largely attributed to normal breast tissue having the highest occurrence of IR events compared to other healthy tissues. Our analyses suggest that low numbers of IR events in breast tumours are associated with poor prognosis, particularly in the luminal B subtype. Interestingly, we found that IR frequencies negatively correlate with cell proliferation in BrCa cells, i.e. rapidly iding tumour cells have the lowest number of IR events. Aberrant RNA-binding protein expression and changes in tissue composition are among the causes of aberrantly decreasing IR in BrCa. Our results suggest that IR should be considered for therapeutic manipulation in BrCa patients with aberrantly low IR levels and that further work is needed to understand the cause and impact of high IR in other tumour types.
Publisher: Elsevier BV
Date: 2014
DOI: 10.1016/J.BBAPAP.2013.05.007
Abstract: A decade of successful results indicates that systems biology is the appropriate approach to investigate the regulation of complex biochemical networks involving transcriptional and post-transcriptional regulations. It becomes mandatory when dealing with highly interconnected biochemical networks, composed of hundreds of compounds, or when networks are enriched in non-linear motifs like feedback and feedforward loops. An emerging dilemma is to conciliate models of massive networks and the adequate description of non-linear dynamics in a suitable modeling framework. Boolean networks are an ideal representation of massive networks that are humble in terms of computational complexity and data demand. However, they are inappropriate when dealing with nested feedback/feedforward loops, structural motifs common in biochemical networks. On the other hand, models of ordinary differential equations (ODEs) cope well with these loops, but they require enormous amounts of quantitative data for a full characterization of the model. Here we propose hybrid models, composed of ODE and logical sub-modules, as a strategy to handle large scale, non-linear biochemical networks that include transcriptional and post-transcriptional regulations. We illustrate the construction of this kind of models using as ex le a regulatory network centered on E2F1, a transcription factor involved in cancer. The hybrid modeling approach proposed is a good compromise between quantitative/qualitative accuracy and scalability when considering large biochemical networks with a small highly interconnected core, and module of transcriptionally regulated genes that are not part of critical regulatory loops. This article is part of a Special Issue entitled: Computational Proteomics, Systems Biology & Clinical Implications. Guest Editor: Yudong Cai.
Publisher: Oxford University Press (OUP)
Date: 09-2016
DOI: 10.1093/BIB/BBV061
Abstract: There was evidence that RNAs are a functionally rich class of molecules not only since the arrival of the next-generation sequencing technology. Non-coding RNAs (ncRNA) could be the key to accelerated diagnosis and enhanced prediction of disease and therapy outcomes as well as the design of advanced therapeutic strategies to overcome yet unsatisfactory approaches.In this review, we discuss the state of the art in RNA systems biology with focus on the application in the systems biomedicine field. We propose guidelines for analysing the role of microRNAs and long non-coding RNAs in human pathologies. We introduce RNA expression profiling and network approaches for the identification of stable and effective RNomics-based biomarkers, providing insights into the role of ncRNAs in disease regulation. Towards this, we discuss ways to model the dynamics of gene regulatory networks and signalling pathways that involve ncRNAs. We also describe data resources and computational methods for finding putative mechanisms of action of ncRNAs. Finally, we discuss avenues for the computer-aided design of novel RNA-based therapeutics.
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: Cold Spring Harbor Laboratory
Date: 16-11-2021
DOI: 10.1101/2021.11.15.468579
Abstract: In pancreatic cancer, emerging evidence suggests that PPAR-δ overexpression is associated with tumor progression and metastasis, but a mechanistic link is still missing. Here we now show that PPAR-δ acts as the integrating upstream regulator for the metabolic rewiring, which is preceding the subsequent initiation of an invasive/metastatic program. Specifically, paracrine and metabolic cues regularly found in the metastasis-promoting tumor stroma consistently enhance, via induction of PPAR-δ activity, the glycolytic capacity and reserve of pancreatic cancer cells, respectively, accompanied by decreased mitochondrial oxygen consumption. Consequently, genetic or pharmacological inhibition of PPAR-δ results in reduced invasiveness and metastasis. Mechanistically, PPAR-δ acts by shifting the MYC/PGC1A balance towards MY C, enhancing metabolic plasticity. Targeting MYC similarly prevents the metabolic switch and subsequent initiation of invasiveness. Therefore, our data demonstrate that PPAR-δ is a key initiator for the metabolic reprogramming in pancreatic cancer, thereby acting as a checkpoint for the phenotypic change towards invasiveness. These findings provide compelling evidence for a novel treatment strategy to combat pancreatic cancer progression.
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: Springer Science and Business Media LLC
Date: 29-09-2010
Abstract: Non-coding RNAs gain more attention as their erse roles in many cellular processes are discovered. At the same time, the need for efficient computational prediction of ncRNAs increases with the pace of sequencing technology. Existing tools are based on various approaches and techniques, but none of them provides a reliable ncRNA detector yet. Consequently, a natural approach is to combine existing tools. Due to a lack of standard input and output formats combination and comparison of existing tools is difficult. Also, for genomic scans they often need to be incorporated in detection workflows using custom scripts, which decreases transparency and reproducibility. We developed a Java-based framework to integrate existing tools and methods for ncRNA detection. This framework enables users to construct transparent detection workflows and to combine and compare different methods efficiently. We demonstrate the effectiveness of combining detection methods in case studies with the small genomes of Escherichia coli , Listeria monocytogenes and Streptococcus pyogenes . With the combined method, we gained 10% to 20% precision for sensitivities from 30% to 80%. Further, we investigated Streptococcus pyogenes for novel ncRNAs. Using multiple methods--integrated by our framework--we determined four highly probable candidates. We verified all four candidates experimentally using RT-PCR. We have created an extensible framework for practical, transparent and reproducible combination and comparison of ncRNA detection methods. We have proven the effectiveness of this approach in tests and by guiding experiments to find new ncRNAs. The software is freely available under the GNU General Public License (GPL), version 3 at www.sbi.uni-rostock.de/moses along with source code, screen shots, ex les and tutorial material.
Publisher: American Association for Cancer Research (AACR)
Date: 15-02-2021
DOI: 10.1158/0008-5472.CAN-20-1943
Abstract: Intron retention (IR) in cancer was for a long time overlooked by the scientific community, as it was previously considered to be an artifact of a dysfunctional spliceosome. Technological advancements made in the last decade offer unique opportunities to explore the role of IR as a widespread phenomenon that contributes to the transcriptional ersity of many cancers. Numerous studies in cancer have shed light on dysregulation of cellular mechanisms that lead to aberrant and pathologic IR. IR is not merely a mechanism of gene regulation, but rather it can mediate cancer pathogenesis and therapeutic resistance in various human diseases. The burden of IR in cancer is governed by perturbations to mechanisms known to regulate this phenomenon and include epigenetic variation, mutations within the gene body, and splicing factor dysregulation. This review summarizes possible causes for aberrant IR and discusses the role of IR in therapy or as a consequence of disease treatment. As neoepitopes originating from retained introns can be presented on the cancer cell surface, the development of personalized cancer vaccines based on IR-derived neoepitopes should be considered. Ultimately, a deeper comprehension about the origins and consequences of aberrant IR may aid in the development of such personalized cancer vaccines.
Publisher: Springer Science and Business Media LLC
Date: 26-06-2023
DOI: 10.1038/S41416-023-02311-0
Abstract: To determine the safety and efficacy of PARP plus PD-L1 inhibition (olaparib + durvalumab, O + D) in patients with advanced solid, predominantly rare cancers harbouring homologous recombination repair (HRR) defects. In total, 48 patients were treated with O + D, 16 with BRCA1/2 alterations (group 1) and 32 with other select HRR alterations (group 2). Overall, 32 (66%) patients had rare or less common cancers. The primary objective of this single-arm Phase II trial was a progression-free survival rate at 6 months (PFS6). Post hoc exploratory analyses were conducted on archival tumour tissue and serial bloods. The PFS6 rate was 35% and 38% with durable objective tumour responses (OTR) in 3(19%) and 3(9%) in groups 1 and 2, respectively. Rare cancers achieving an OTR included cholangiocarcinoma, perivascular epithelioid cell (PEComa), neuroendocrine, gallbladder and endometrial cancer. O + D was safe, with five serious adverse events related to the study drug(s) in 3 (6%) patients. A higher proportion of CD38 high B cells in the blood and higher CD40 expression in tumour was prognostic of survival. O + D demonstrated no new toxicity concerns and yielded a clinically meaningful PFS6 rate and durable OTRs across several cancers with HRR defects, including rare cancers.
Publisher: Mary Ann Liebert Inc
Date: 12-2012
Abstract: In an "aging society," health span extension is most important. As in 2010, talks in this series of meetings in Rostock-Warnemünde demonstrated that aging is an apparently very complex process, where computational work is most useful for gaining insights and to find interventions that counter aging and prevent or counteract aging-related diseases. The specific topics of this year's meeting entitled, "RoSyBA: Rostock Symposium on Systems Biology and Bioinformatics in Ageing Research," were primarily related to "Cancer and Aging" and also had a focus on work funded by the German Federal Ministry of Education and Research (BMBF). The next meeting in the series, scheduled for September 20-21, 2013, will focus on the use of ontologies for computational research into aging, stem cells, and cancer. Promoting knowledge formalization is also at the core of the set of proposed action items concluding this report.
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: Wiley
Date: 15-08-2014
Publisher: Ivyspring International Publisher
Date: 2018
DOI: 10.7150/THNO.19904
Publisher: Springer International Publishing
Date: 2022
Publisher: Elsevier BV
Date: 08-2022
DOI: 10.1016/J.TIG.2022.03.017
Abstract: Recent landmark discoveries have underpinned the physiological importance of intron retention (IR) across multiple domains of life and revealed an unexpected breath of functions in a large variety of biological processes. Despite significant progress in the field, some challenges remain. Once solved, opportunities will arise for discovering more functions of IR.
Publisher: Cold Spring Harbor Laboratory
Date: 08-01-2021
DOI: 10.1101/2021.01.08.425848
Abstract: Human cancers commonly contain mutations in transcription factors that lead to aberrant DNA binding or altered effector function at target sites. One such factor significantly mutated in cancer is the evolutionarily-conserved CCCTC-binding factor (CTCF), which has fundamental roles in maintaining chromatin architecture and transcriptional regulation. Numerous cancer genome sequencing and functional studies have revealed CTCF’s role as a haploinsufficient tumour suppressor gene. However, to date, structure-function relationships of somatic CTCF mutations have not been examined. We collated somatic CTCF mutations from cancer genome portals and published studies to determine their nature, frequency, distribution and potential functional impact. We undertook an in-depth examination of 5 CTCF missense zinc finger (ZF) mutations occurring within key intra- and inter-ZF residues. We performed functional analyses including cell growth, colony-formation, chromatin immunoprecipitation and transcriptional reporter assays. Based on their homology, each ZF mutation was then modelled on CTCF’s ZF domain crystal structure and its structural impact analysed using molecular dynamics simulations. We observed an enrichment of somatic missense mutations occurring in the ZF region of CTCF, compared to the unstructured N- and C-termini. Functional characterisation of CTCF ZF mutations revealed a complete (L309P, R339W, R377H) or intermediate (R339Q) abrogation as well as an enhancement (G420D) of the anti-proliferative effects of CTCF. DNA binding at select sites was disrupted and transcriptional regulatory activities abrogated. In silico mutagenesis revealed that L309P had the highest mutation energy and thus most severe impact on protein stability. Molecular docking and molecular dynamics simulations confirmed that mutations in residues specifically contacting DNA bases or backbone exhibited loss of DNA binding (R339Q, R339W, R377H). Remarkably, R339Q and G420D were stabilised by the formation of new primary DNA bonds. All mutations exhibited some loss or gain of bonds at neighbouring residues, often in adjacent zinc fingers. Our data confirm the significant negative impact haploinsufficient CTCF ZF mutations have on its tumour suppressor function. A spectrum of loss-, change- and gain-of-function impacts in CTCF zinc fingers are observed in cell growth regulation and gene regulatory activities. We have established that erse cellular phenotypes in CTCF are explained by examining structure-function relationships.
Publisher: MDPI AG
Date: 19-08-2019
DOI: 10.3390/CELLS8080929
Abstract: Colorectal cancer (CRC) results from a transformation of colonic epithelial cells into adenocarcinoma cells due to genetic and epigenetic instabilities, alongside remodelling of the surrounding stromal tumour microenvironment. Epithelial-specific epigenetic variations escorting this process include chromatin remodelling, histone modifications and aberrant DNA methylation, which influence gene expression, alternative splicing and function of non-coding RNA. In this review, we first highlight epigenetic modulators, modifiers and mediators in CRC, then we elaborate on causes and consequences of epigenetic alterations in CRC pathogenesis alongside an appraisal of the complex feedback mechanisms realized through alternative splicing and non-coding RNA regulation. An emphasis in our review is put on how this intricate network of epigenetic and post-transcriptional gene regulation evolves during the initiation, progression and metastasis formation in CRC.
Publisher: Cold Spring Harbor Laboratory
Date: 04-08-2020
DOI: 10.1101/2020.07.31.20165597
Abstract: Vast transcriptomics and epigenomics changes are characteristic of human cancers including leukemia. 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 leukemia (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: MDPI AG
Date: 19-03-2023
Abstract: The microsatellite stable/epithelial-mesenchymal transition (MSS/EMT) subtype of gastric cancer represents a highly aggressive class of tumors associated with low rates of survival and considerably high probabilities of recurrence. In the era of precision medicine, the accurate and prompt diagnosis of tumors of this subtype is of vital importance. In this study, we used Weighted Gene Co-expression Network Analysis (WGCNA) to identify a differentially expressed co-expression module of mRNAs in EMT-type gastric tumors. Using network analysis and linear discriminant analysis, we identified mRNA motifs and microRNA-based models with strong prognostic and diagnostic relevance: three models comprised of (i) the microRNAs miR-199a-5p and miR-141-3p, (ii) EVC/EVC2/GLI3, and (iii) PDE2A/GUCY1A1/GUCY1B1 gene expression profiles distinguish EMT-type tumors from other gastric tumors with high accuracy (Area Under the Receiver Operating Characteristic Curve (AUC) = 0.995, AUC = 0.9742, and AUC = 0.9717 respectively). Additionally, the DMD/ITGA1/CAV1 motif was identified as the top motif with consistent relevance to prognosis (hazard ratio 3). Molecular functions of the members of the identified models highlight the central roles of MAPK, Hh, and cGMP/cAMP signaling in the pathology of the EMT subtype of gastric cancer and underscore their potential utility in precision therapeutic approaches.
Publisher: Elsevier BV
Date: 07-2011
DOI: 10.1016/J.MEEGID.2011.03.018
Abstract: Antigenic drift causes number of mutations in neuraminidase protein of H1N1 swine influenza virus. We analyzed neuraminidase mutations in H1N1 strains distributed over six continents, at both the sequence and structural level. Mutations in the nearby residues of the drug binding site play crucial role in the binding affinity of the drug with the protein. For this purpose, mutant models were generated for the neuraminidase protein from 34 pandemic H1N1 isolates and docking were performed with zanamivir drug. Multiple sequence alignment (MSA) and variations in docking score suggest that there are considerable changes in the binding affinity of neuraminidase with zanamivir, which leads to probable ineffectiveness of zanamivir in the isolated s les of pandemic H1N1 collected from quite a few countries. To further evaluate the effectiveness of the antiviral drugs, we derived, calibrated and analyzed an ordinary differential equations based mathematical model for H1N1 infection dynamics and drug mediated virus deactivation.
Publisher: MDPI AG
Date: 10-11-2021
Abstract: Chimeric RNAs are often associated with chromosomal rearrangements in cancer. In addition, they are also widely detected in normal tissues, contributing to transcriptomic complexity. Despite their prevalence, little is known about the characteristics and functions of chimeric RNAs. Here, we examine the genetic structure and biological roles of CLEC12A-MIR223HG, a novel chimeric transcript produced by the fusion of the cell surface receptor CLEC12A and the miRNA-223 host gene (MIR223HG), first identified in chronic myeloid leukemia (CML) patients. Surprisingly, we observed that CLEC12A-MIR223HG is not just expressed in CML, but also in a variety of normal tissues and cell lines. CLEC12A-MIR223HG expression is elevated in pro-monocytic cells resistant to chemotherapy and during monocyte-to-macrophage differentiation. We observed that CLEC12A-MIR223HG is a product of trans-splicing rather than a chromosomal rearrangement and that transcriptional activation of CLEC12A with the CRISPR/Cas9 Synergistic Activation Mediator (SAM) system increases CLEC12A-MIR223HG expression. CLEC12A-MIR223HG translates into a chimeric protein, which largely resembles CLEC12A but harbours an altered C-type lectin domain altering key disulphide bonds. These alterations result in differences in post-translational modifications, cellular localization, and protein–protein interactions. Taken together, our observations support a possible involvement of CLEC12A-MIR223HG in the regulation of CLEC12A function. Our workflow also serves as a template to study other uncharacterized chimeric RNAs.
Publisher: Informa UK Limited
Date: 20-08-2021
Publisher: Inderscience Publishers
Date: 2009
Publisher: Springer New York
Date: 2013
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: Impact Journals, LLC
Date: 24-03-2015
Abstract: Mutations of mitochondrial (mt)DNA cause a variety of human diseases and are implicated in premature aging syndromes. Here we investigated a single nucleotide exchange (leucine to methionine) at position nt4738 in the mitochondrial NADH dehydrogenase subunit 2 (Nd2) gene of the respiratory chain. Primary fibroblasts derived from the conplastic mouse strain C57BL/6J-mtALR/LTJ with mutant enzyme, possessed high enzyme activity and ATP production and low ROS production. Furthermore, Nd2-mutant fibroblasts expressed lower senescence markers. Transcriptome analysis revealed that the members of the p38MAPK pathway were significantly downregulated in Nd2-mutant mice. In agreement, inhibition of p38MAPK with SB203580 enhanced proliferation and reduced cytokine secretion in fibroblasts. In Nd2-mutant mouse skin, the amount of Ki67-positive cells was significantly higher than in control skin. The higher amount of Ki67-positive cells and the thicker epidermis in Nd2-mutant mice strongly supported the in vitro data. In conclusion, Nd2 is a mitochondrial gene, involved in age-related signaling pathways.
Publisher: Springer Science and Business Media LLC
Date: 23-11-2016
Publisher: Oxford University Press (OUP)
Date: 28-01-2016
DOI: 10.1093/NAR/GKW041
Publisher: No publisher found
Date: 2013
DOI: 10.1007/978-94-007-5590-1_12
Abstract: Over the last decade thousands of microRNAs (miRNAs) have been discovered in all kinds of taxa. The ever growing number of identified miRNA genes required ordered cataloging and annotation. This has led to the development of miRNA web resources.MiRNA web resources can be referred to either as web accessible databases (repositories) or web applications that provide a defined computational task upon user request. Today, more than three dozen web accessible resources exist that gather, organize and annotate all kinds of miRNA related data. According to the type of data or data processing method, these miRNA web resources can be classified as miRNA sequence and annotation databases, resources and tools for predicted as well as experimentally validated targets, databases of miRNA regulation and expression, functional annotation and mapping databases and a number of other tools and resources that are species-specific or focus on particular phenotypes.This chapter provides an overview of the different types of miRNA web resources and their purpose and gives some ex les for each category. Furthermore, some valuable miRNA web applications will be introduced. Finally, strategies for miRNA data retrieval and associated risks and pitfalls will be discussed.
Publisher: Springer New York
Date: 2017
DOI: 10.1007/978-1-4939-6866-4_11
Abstract: In this chapter we discuss computational methods for the prediction of microRNA (miRNA) targets. More specifically, we consider machine learning-based approaches and explain why these methods have been relatively unsuccessful in reducing the number of false positive predictions. Further we suggest approaches designed to improve their performance by considering tissue-specific target regulation. We argue that the miRNA targetome differs depending on the tissue type and introduce a novel algorithm that predicts miRNA targets specifically for colorectal cancer. We discuss features of miRNAs and target sites that affect target recognition, and how next-generation sequencing data can support the identification of novel miRNAs, differentially expressed miRNAs and their tissue-specific mRNA targets. In addition, we introduce some experimental approaches for the validation of miRNA targets as well as web-based resources sharing predicted and validated miRNA target interactions.
Publisher: Oxford University Press (OUP)
Date: 24-07-2019
DOI: 10.1093/NAR/GKZ638
Abstract: MicroRNAs (miRNAs) are short, noncoding RNAs that regulate gene expression by suppressing mRNA translation and reducing mRNA stability. A miRNA can potentially bind many mRNAs, thereby affecting the expression of oncogenes and tumor suppressor genes as well as the activity of whole pathways. The promise of miRNA therapeutics in cancer is to harness this evolutionarily conserved mechanism for the coordinated regulation of gene expression, and thus restoring a normal cell phenotype. However, the promiscuous binding of miRNAs can provoke unwanted off-target effects, which are usually caused by high-dose single-miRNA treatments. Thus, it is desirable to develop miRNA therapeutics with increased specificity and efficacy. To achieve that, we propose the concept of miRNA cooperativity in order to exert synergistic repression on target genes, thus lowering the required total amount of miRNAs. We first review miRNA therapies in clinical application. Next, we summarize the knowledge on the molecular mechanism and biological function of miRNA cooperativity and discuss its application in cancer therapies. We then propose and discuss a systems biology approach to investigate miRNA cooperativity for the clinical setting. Altogether, we point out the potential of miRNA cooperativity to reduce off-target effects and to complement conventional, targeted, or immune-based therapies for cancer.
Publisher: MDPI AG
Date: 28-07-2020
Abstract: Background: Survival from melanoma is strongly related to patient sex, with females having a survival rate almost twice that of males. Many explanations have been proposed but have not withstood critical scrutiny. Prior analysis of different cancers with a sex bias has identified six X-linked genes that escape X chromosome inactivation in females and are, therefore, potentially involved in sex differences in survival. Four of the genes are well-known epigenetic regulators that are known to influence the expression of hundreds of other genes and signaling pathways in cancer. Methods: Survival and interaction analysis were performed on the skin cutaneous melanoma (SKCM) cohort in The Cancer Genome Atlas (TCGA), comparing high vs. low expression of KDM6A, ATRX, KDM5C, and DDX3X. The Leeds melanoma cohort (LMC) on 678 patients with primary melanoma was used as a validation cohort. Results: Analysis of TCGA data revealed that two of these genes—KDM6A and ATRX—were associated with improved survival from melanoma. Tumoral KDM6A was expressed at higher levels in females and was associated with inferred lymphoid infiltration into melanoma. Gene set analysis of high KDM6A showed strong associations with immune responses and downregulation of genes associated with Myc and other oncogenic pathways. The LMC analysis confirmed the prognostic significance of KDM6A and its interaction with EZH2 but also revealed the expression of KDM5C and DDX3X to be prognostically significant. The analysis also confirmed a partial correlation of KDM6A with immune tumor infiltrates. Conclusion: When considered together, the results from these two series are consistent with the involvement of X-linked epigenetic regulators in the improved survival of females from melanoma. The identification of gene signatures associated with their expression presents insights into the development of new treatment initiatives but provides a basis for exploration in future studies.
Publisher: Springer Science and Business Media LLC
Date: 24-02-2010
DOI: 10.1007/S10585-010-9310-7
Abstract: A large-scale gene expression study of melanoma metastases was performed to identify genes involved in late-stage tumor progression. Overall 248 genes, out of more than 47,000 tested, are differentially expressed when comparing peripheral areas (invasion front) with central tumor areas of melanoma metastases. As determined by gene ontology analysis, members of the STAT signaling pathway show significant enrichment. In particular, Stat1 is highly expressed in peripheral compared with central tumor areas. In line with this, stable knockdown of STAT1 in metastatic melanoma cells significantly impairs their migratory and invasive capacity in wounding and matrigel assays. Moreover, STAT1 knockdown affects the metastatic behavior of melanoma cells in a mouse model of melanoma metastasis. Taken together, these data suggest that Stat1 might play a role in late-stage melanoma progression. Interference with the Stat1 pathway could have therapeutic implications for late-stage melanoma patients.
Publisher: Springer Science and Business Media LLC
Date: 16-11-2017
Publisher: Wiley
Date: 23-01-2015
DOI: 10.1002/GCC.22231
Abstract: MicroRNAs (miRNA/miR) play an important role in gene regulatory networks through targeting mRNAs. They are involved in erse biological processes such as cell proliferation, differentiation, angiogenesis, and apoptosis. Due to their pivotal effects on multiple genes and pathways, dysregulated miRNAs have been reported to be associated with different diseases, including colorectal cancer (CRC). Recent evidence indicates that aberrant miRNA expression is tightly linked with the initiation and progression of CRC. To elucidate the influence of miRNA regulation in CRC, it is critical to identify dysregulated miRNAs, their target mRNA genes and their involvement in gene regulatory and signaling networks. Various experimental and computational studies have been conducted to decipher the function of miRNAs involved in CRC. Experimental studies that are used for this purpose can be classified into two categories: direct/in idual and indirect/high-throughput gene expression studies. Here we review miRNA target identification studies related to CRC with an emphasis on experimental data based on Luciferase reporter assays. Recent advances in determining the function of miRNAs and the signaling pathways they are involved in have also been summarized. The review helps bioinformaticians and biologists to find extensive information about downstream targets of dysregulated miRNAs, and their pro-/anti-CRC effects.
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/0008-5472.22427131
Abstract: IR in CAR-T cell treatment and a possible approach to therapy. Development of antisense oligonucleotides-based therapies to correct pathological IR events.
Publisher: Cold Spring Harbor Laboratory
Date: 18-02-2021
DOI: 10.1101/2021.02.17.431609
Abstract: Dynamic intron retention (IR) in vertebrate cells is of widespread biological importance. Aberrant IR is associated with numerous human diseases including cancer. Despite consistent reports demonstrating intrinsic sequence features that predispose introns to become retained, conflicting findings about cell type-specific IR regulation demand a systematic analysis in a controlled experimental setting. We integrated matched transcriptomics and epigenetics data (including DNA methylation, nucleosome occupancy, histone modifications) from primary human myeloid and lymphoid cells. Using machine learning we trained two complementary models to determine the role of epigenetic factors in the regulation of IR. We show that increased chromatin accessibility 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. With mounting reports linking pathogenic alterations to RNA processing, our findings may have profound implications for the design of therapeutic approaches targeting aberrant splicing.
Publisher: Oxford University Press (OUP)
Date: 29-05-2014
DOI: 10.1093/NAR/GKU465
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/0008-5472.22427131.V1
Abstract: IR in CAR-T cell treatment and a possible approach to therapy. Development of antisense oligonucleotides-based therapies to correct pathological IR events.
Publisher: Public Library of Science (PLoS)
Date: 22-12-2016
Publisher: Springer Netherlands
Date: 19-12-2013
DOI: 10.1007/978-94-007-5590-1_4
Abstract: MicroRNAs (miRNAs) are involved in many regulatory pathways some of which are complex networks enriched in regulatory motifs like positive or negative feedback loops or coherent and incoherent feedforward loops. Their complexity makes the understanding of their regulation difficult and the interpretation of experimental data cumbersome. In this book chapter we claim that systems biology is the appropriate approach to investigate the regulation of these miRNA-regulated networks. Systems biology is an interdisciplinary approach by which biomedical questions on biochemical networks are addressed by integrating experiments with mathematical modelling and simulation. We here introduce the foundations of the systems biology approach, the basic theoretical and computational tools used to perform model-based analyses of miRNA-regulated networks and review the scientific literature in systems biology of miRNA regulation, with a focus on cancer.
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: Springer Science and Business Media LLC
Date: 06-01-2016
Publisher: American Association for Cancer Research (AACR)
Date: 13-06-2013
DOI: 10.1158/0008-5472.CAN-12-4095
Abstract: Drug resistance is a major cause of deaths from cancer. E2F1 is a transcription factor involved in cell proliferation, apoptosis. and metastasis through an intricate regulatory network, which includes other transcription factors like p73 and cancer-related microRNAs like miR-205. To investigate the emergence of drug resistance, we developed a methodology that integrates experimental data with a network biology and kinetic modeling. Using a regulatory map developed to summarize knowledge on E2F1 and its interplay with p73/DNp73 and miR-205 in cancer drug responses, we derived a kinetic model that represents the network response to certain genotoxic and cytostatic anticancer drugs. By perturbing the model parameters, we simulated heterogeneous cell configurations referred to as in silico cell lines. These were used to detect genetic signatures characteristic for single or double drug resistance. We identified a signature composed of high E2F1 and low miR-205 expression that promotes resistance to genotoxic drugs. In this signature, downregulation of miR-205, can be mediated by an imbalance in the p73/DNp73 ratio or by dysregulation of other cancer-related regulators of miR-205 expression such as TGFβ-1 or TWIST1. In addition, we found that a genetic signature composed of high E2F1, low miR-205, and high ERBB3 can render tumor cells insensitive to both cytostatic and genotoxic drugs. Our model simulations also suggested that conventional genotoxic drug treatment favors selection of chemoresistant cells in genetically heterogeneous tumors, in a manner requiring dysregulation of incoherent feedforward loops that involve E2F1, p73/DNp73, and miR-205. Cancer Res 73(12) 3511–24. ©2013 AACR.
Publisher: Springer Science and Business Media LLC
Date: 04-08-2017
DOI: 10.1038/S41467-017-00268-2
Abstract: Cancer is a disease of subverted regulatory pathways. In this paper, we reconstruct the regulatory network around E2F, a family of transcription factors whose deregulation has been associated to cancer progression, chemoresistance, invasiveness, and metastasis. We integrate gene expression profiles of cancer cell lines from two E2F1-driven highly aggressive bladder and breast tumors, and use network analysis methods to identify the tumor type-specific core of the network. By combining logic-based network modeling, in vitro experimentation, and gene expression profiles from patient cohorts displaying tumor aggressiveness, we identify and experimentally validate distinctive, tumor type-specific signatures of receptor proteins associated to epithelial–mesenchymal transition in bladder and breast cancer. Our integrative network-based methodology, exemplified in the case of E2F1-induced aggressive tumors, has the potential to support the design of cohort- as well as tumor type-specific treatments and ultimately, to fight metastasis and therapy resistance.
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/0008-5472.C.6512560.V1
Abstract: Abstract Intron retention (IR) in cancer was for a long time overlooked by the scientific community, as it was previously considered to be an artifact of a dysfunctional spliceosome. Technological advancements made in the last decade offer unique opportunities to explore the role of IR as a widespread phenomenon that contributes to the transcriptional ersity of many cancers. Numerous studies in cancer have shed light on dysregulation of cellular mechanisms that lead to aberrant and pathologic IR. IR is not merely a mechanism of gene regulation, but rather it can mediate cancer pathogenesis and therapeutic resistance in various human diseases. The burden of IR in cancer is governed by perturbations to mechanisms known to regulate this phenomenon and include epigenetic variation, mutations within the gene body, and splicing factor dysregulation. This review summarizes possible causes for aberrant IR and discusses the role of IR in therapy or as a consequence of disease treatment. As neoepitopes originating from retained introns can be presented on the cancer cell surface, the development of personalized cancer vaccines based on IR-derived neoepitopes should be considered. Ultimately, a deeper comprehension about the origins and consequences of aberrant IR may aid in the development of such personalized cancer vaccines. /
Publisher: Springer New York
Date: 2013
Publisher: Oxford University Press (OUP)
Date: 14-07-2015
DOI: 10.1093/BIB/BBV046
Abstract: The immune system is by definition multi-scale because it involves biochemical networks that regulate cell fates across cell boundaries, but also because immune cells communicate with each other by direct contact or through the secretion of local or systemic signals. Furthermore, tumor and immune cells communicate, and this interaction is affected by the tumor microenvironment. Altogether, the tumor-immunity interaction is a complex multi-scale biological system whose analysis requires a systemic view to succeed in developing efficient immunotherapies for cancer and immune-related diseases. In this review we discuss the necessity and the structure of a systems medicine approach for the design of anticancer immunotherapies. We support the idea that the approach must be a combination of algorithms and methods from bioinformatics and patient-data-driven mathematical models conceived to investigate the role of clinical interventions in the tumor-immunity interaction. For each step of the integrative approach proposed, we review the advancement with respect to the computational tools and methods available, but also successful case studies. We particularized our idea for the case of identifying novel tumor-associated antigens and therapeutic targets by integration of patient's immune and tumor profiling in case of aggressive melanoma.
Publisher: Elsevier BV
Date: 2023
Publisher: Springer Science and Business Media LLC
Date: 26-09-2016
DOI: 10.1007/S12603-016-0803-1
Abstract: The Strategic Implementation Plan of the European Innovation Partnership on Active and Healthy Ageing (EIP on AHA) proposed six Action Groups. After almost three years of activity, many achievements have been obtained through commitments or collaborative work of the Action Groups. However, they have often worked in silos and, consequently, synergies between Action Groups have been proposed to strengthen the triple win of the EIP on AHA. The paper presents the methodology and current status of the Task Force on EIP on AHA synergies. Synergies are in line with the Action Groups' new Renovated Action Plan (2016-2018) to ensure that their future objectives are coherent and fully connected. The outcomes and impact of synergies are using the Monitoring and Assessment Framework for the EIP on AHA (MAFEIP). Eight proposals for synergies have been approved by the Task Force: Five cross-cutting synergies which can be used for all current and future synergies as they consider overarching domains (appropriate polypharmacy, citizen empowerment, teaching and coaching on AHA, deployment of synergies to EU regions, Responsible Research and Innovation), and three cross-cutting synergies focussing on current Action Group activities (falls, frailty, integrated care and chronic respiratory diseases).
Publisher: Hindawi Limited
Date: 2013
DOI: 10.1155/2013/703849
Abstract: MicroRNAs (miRNAs) are potent effectors in gene regulatory networks where aberrant miRNA expression can contribute to human diseases such as cancer. For a better understanding of the regulatory role of miRNAs in coordinating gene expression, we here present a systems biology approach combining data-driven modeling and model-driven experiments. Such an approach is characterized by an iterative process, including biological data acquisition and integration, network construction, mathematical modeling and experimental validation. To demonstrate the application of this approach, we adopt it to investigate mechanisms of collective repression on p21 by multiple miRNAs. We first construct a p21 regulatory network based on data from the literature and further expand it using algorithms that predict molecular interactions. Based on the network structure, a detailed mechanistic model is established and its parameter values are determined using data. Finally, the calibrated model is used to study the effect of different miRNA expression profiles and cooperative target regulation on p21 expression levels in different biological contexts.
Publisher: Elsevier BV
Date: 03-2011
DOI: 10.1016/J.MEEGID.2010.10.013
Abstract: Antigenic drift is the ability of the swine influenza virus to undergo continuous and progressive changes in response to the host immune system. These changes dictate influenza vaccine updates annually to ensure inclusion of antigens of the most current strains. The identification of those peptides that stimulate T-cell responses, termed T-cell epitopes, is essential for the development of successful vaccines. In this study, the highly conserved and specific epitopes from neuraminidase of globally distributed H1N1 strains were predicted so that these potential vaccine candidates may escape with antigenic drift. A total of nine novel CD8(+) T-cell epitopes for MHC class-I and eight novel CD4(+) T-cell epitopes for MHC class-II alleles were proposed as novel epitope based vaccine candidates. Additionally, the epitope FSYKYGNGV was identified as a highly conserved, immunogenic and potential vaccine candidate, capable for generating both CD8(+) and CD4(+) responses.
Publisher: CMB Association
Date: 30-10-2015
Publisher: Informa UK Limited
Date: 15-08-2012
DOI: 10.4161/CC.21476
Publisher: Springer New York
Date: 2013
Publisher: Cold Spring Harbor Laboratory
Date: 05-03-2022
DOI: 10.1101/2022.03.04.482791
Abstract: After many years of neglect in the field of alternative splicing, the importance of intron retention (IR) in cancer has come into focus following landmark discoveries of aberrant IR patterns in cancer. Many solid and liquid tumours are associated with drastic increases in IR and such patterns have been pursued as both biomarkers and therapeutic targets. Paradoxically, breast cancer (BrCa) is the only tumour type in which IR is reduced compared to adjacent normal breast tissue. In this study, we have conducted a pan-cancer analysis of IR with emphasis on BrCa and its subtypes. We explored mechanisms that could cause aberrant and pathological IR and clarified why normal breast tissue has unusually high IR. Strikingly, we found that reduced IR in BrCa can be largely attributed to normal breast tissue having the highest occurrence of IR events compared to other healthy tissues. Our analyses suggest that low numbers of IR events in breast tumours are associated with poor prognosis, particularly in the luminal B subtype. Interestingly, we found that IR frequencies negatively correlate with cell proliferation in BrCa cells, i.e. rapidly iding tumour cells have the lowest number of IR events. Aberrant RNA binding protein (RBP) expression and changes in tissue composition are among the causes of low IR in BrCa. Our results suggest that IR should be considered for therapeutic manipulation in BrCa patients with aberrantly low IR levels and that further work is needed to understand the cause and impact of high IR in other tumour types.
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: 2023
Publisher: Springer Science and Business Media LLC
Date: 31-08-2010
DOI: 10.1007/S12064-010-0109-5
Abstract: In this paper we present and discuss a model-based approach to link miRNA translational control with cell signalling networks. MicroRNAs are small regulatory RNAs that are able to regulate the activity and the stability of specific messenger RNA and have been implicated in tumour progression due to their ability to translationally regulate critical oncogenes and tumour suppressors. In our approach, data on protein-protein interactions and miRNA regulation, obtained from bioinformatics databases, are integrated with quantitative experimental data using mathematical modelling. Predictive computational simulations and qualitative (bifurcation) analyses of those mathematical models are employed to further support the investigation of such multifactorial networks in the context of cancer progression. We illustrate our approach with the C-Myc/E2F signalling network, involved in the progression of several tumour subtypes, including colorectal cancer.
Publisher: EMBO
Date: 23-10-2014
Abstract: Malignant melanoma is highly lethal due to its aggressive invasive properties and metastatic dissemination. The transcription factor E2F1 is crucial for melanoma progression through poorly understood mechanisms. Here, we show that the miR‐224/miR‐452 cluster is significantly increased in advanced melanoma and invasive/metastatic cell lines that express high levels of E2F1. miR‐224/miR‐452 expression is directly activated by E2F1 through transactivation of the GABRE gene. Ectopic expression of miR‐224/miR‐452 in less aggressive cells induces EMT and cytoskeletal rearrangements and enhances migration/invasion. Conversely, miR‐224/miR‐452 depletion in metastatic cells induces the reversal of EMT , inhibition of motility, loss of the invasive phenotype and an absence of lung metastases in mice. We identify the metastasis suppressor TXNIP as new target of miR‐224/miR‐452 that induces feedback inhibition of E2F1 and show that miR‐224/452‐mediated downregulation of TXNIP is essential for E2F1‐induced EMT and invasion. The E2F1‐miR‐224/452‐TXNIP axis constitutes a molecular signature that predicts patient survival and may help to set novel therapies.
Publisher: Oxford University Press (OUP)
Date: 02-07-2019
DOI: 10.1093/BIOINFORMATICS/BTY527
Abstract: Extracellular vesicles (EVs), including exosomes and microvesicles, are potent and clinically valuable tools for early diagnosis, prognosis and potentially the targeted treatment of cancer. The content of EVs is closely related to the type and status of the EV-secreting cell. Circulating exosomes are a source of stable RNAs including mRNAs, microRNAs and long non-coding RNAs (lncRNAs). This review outlines the links between EVs, lncRNAs and cancer. We highlight communication networks involving the tumor microenvironment, the immune system and metastasis. We show ex les supporting the value of exosomal lncRNAs as cancer biomarkers and therapeutic targets. We demonstrate how a system biology approach can be used to model cell–cell communication via exosomal lncRNAs and to simulate effects of therapeutic interventions. In addition, we introduce algorithms and bioinformatics resources for the discovery of tumor-specific lncRNAs and tools that are applied to determine exosome content and lncRNA function. Finally, this review provides a comprehensive collection and guide to databases for exosomal lncRNAs. Supplementary data are available at Bioinformatics online.
Publisher: Springer New York
Date: 2016
DOI: 10.1007/978-1-4939-3283-2_14
Abstract: It is due to the advances in high-throughput omics data generation that RNA species have re-entered the focus of biomedical research. International collaborate efforts, like the ENCODE and GENCODE projects, have spawned thousands of previously unknown functional non-coding RNAs (ncRNAs) with various but primarily regulatory roles. Many of these are linked to the emergence and progression of human diseases. In particular, interdisciplinary studies integrating bioinformatics, systems biology, and biotechnological approaches have successfully characterized the role of ncRNAs in different human cancers. These efforts led to the identification of a new tool-kit for cancer diagnosis, monitoring, and treatment, which is now starting to enter and impact on clinical practice. This chapter is to elaborate on the state of the art in RNA systems biology, including a review and perspective on clinical applications toward an integrative RNA systems medicine approach. The focus is on the role of ncRNAs in cancer.
Start Date: 2017
End Date: 2020
Funder: National Health and Medical Research Council
View Funded ActivityStart Date: 2021
End Date: 2025
Funder: National Health and Medical Research Council
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