The Experts below are selected from a list of 132 Experts worldwide ranked by ideXlab platform
Stephan Beck - One of the best experts on this subject based on the ideXlab platform.
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The Human Epigenome Project: Past, Present, and Future
Reference Module in Biomedical Sciences, 2014Co-Authors: Stephan BeckAbstract:Today, it is widely acknowledged that DNA sequence per se does not provide sufficient information to understand how genomes function and the plethora of phenotypic plasticity they exert in time and space. This has not always been the case and a number of efforts deserve credit for changing that perception over the past decade by generating the tools and data for analyzing and interpreting Epigenomes, the functional form of genomes. Collectively, these efforts developed the infrastructure that made formation of the International Human Epigenome Consortium reality. Here, I revisit some of the key efforts from a personal perspective and apologize in advance where my account is too selective, too opinionated, or simply incomplete.
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Taking the measure of the methylome.
Nature biotechnology, 2010Co-Authors: Stephan BeckAbstract:Two comparative studies from the International Human Epigenome Project find high concordance between different methods for measuring genomic methylation.
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Moving AHEAD with an international Human Epigenome Project
Nature, 2008Co-Authors: Peter A. Jones, Stephan Beck, Trevor K. Archer, Stephen B. Baylin, Shelley L. Berger, Bradley E. Bernstein, John D. Carpten, Susan J. Clark, Joseph F. Costello, Rebecca W. DoergeAbstract:A plan to 'genomicize' epigenomics research and pave the way for breakthroughs in the prevention, diagnosis and treatment of Human disease.
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Future potential of the Human Epigenome Project
Expert review of molecular diagnostics, 2004Co-Authors: Florian Eckhardt, Stephan Beck, Ivo Gut, Kurt BerlinAbstract:Deciphering the information encoded in the Human genome is key for the further understanding of Human biology, physiology and evolution. With the draft sequence of the Human genome completed, elucidation of the epigenetic information layer of the Human genome becomes accessible. Epigenetic mechanisms are mediated by either chemical modifications of the DNA itself or by modifications of proteins that are closely associated with DNA. Defects of the epigenetic regulation involved in processes such as imprinting, X chromosome inactivation, transcriptional control of genes, as well as mutations affecting DNA methylation enzymes, contribute fundamentally to the etiology of many Human diseases. Headed by the Human Epigenome Consortium, the Human Epigenome Project is a joint effort by an international collaboration that aims to identify, catalog and interpret genome-wide DNA methylation patterns of all Human genes in all major tissues. Methylation variable positions are thought to reflect gene activity, tissue type and disease state, and are useful epigenetic markers revealing the dynamic state of the genome. Like single nucleotide polymorphisms, methylation variable positions will greatly advance our ability to elucidate and diagnose the molecular basis of Human diseases.
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Epigenomics: genome-wide study of methylation phenomena.
Current issues in molecular biology, 2002Co-Authors: K L Novik, Alexander Olek, I Nimmrich, B Genc, S Maier, C. Piepenbrock, Stephan BeckAbstract:Epigenetics is one of the key areas of future research that can elucidate how genomes work. It combines genetics and the environment to address complex biological systems such as the plasticity of our genome. While all nucleated Human cells carry the same genome, they express different genes at different times. Much of this is governed by epigenetic changes resulting in differential methylation of our genome--or different Epigenomes. Individual studies over the past decades have already established the involvement of DNA methylation in imprinting, gene regulation, chromatin structure, genome stability and disease, especially cancer. Now, in the wake of the Human Genome Project (HGP), epigenetic phenomena can be studied genome-wide and are giving rise to a new field, epigenomics. Here, we review the current and future potential of this field and introduce the pilot study towards the Human Epigenome Project (HEP).
Sofia Kouidou - One of the best experts on this subject based on the ideXlab platform.
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ORIGINAL PAPER DNA hypermethylation of alternatively spliced and repeat sequences in Humans
2016Co-Authors: Andigoni Malousi, Sofia KouidouAbstract:Abstract DNA methylation is presently accepted as a tentative regulatory parameter in splicing. Recently, we reported significant methylation differences among various exonic splicing-enhancing elements and alternative splic-ing events, based on CpG methylation data from the Human Epigenome Project for chromosomes 6, 20 and 22. Presently, using a different computational approach and the same database, we report: (a) significant increase of hypermethylation in intronic and exonic sequences close to acceptor sites, relative to overall introns and exons, respectively (1,973 CpGs examined); (b) frequent CpGs, mostly hypomethylated, in donors and infrequent CpGs mostly hypermethylated, in acceptors; and (c) hyperme-thylation in cassette exons which are occasionally spliced and have weaker average splicing potential, relative to constitutive exons (p \ 0.0001). CpGs are hypomethylated in non-coding exons (only 16 % hypermethylation). Sin-gle-exon genes, similarly to first exons, frequently contain hypomethylated CpGs, while in internal and last exons CpGs are more frequently hypermethylated. Methylation is also more frequent in strange introns and splice sites pro-cessed by the minor spliceosome, e.g., ATAC, (p \ 0.0001 in all cases), but not in sites of incomplete processing, e.g., retained introns or bleeding exons, (p = 0.706 and p = 0.313, respectively). Most Alus, which are known to contribute to transcript presentation, are heavily methylated, in contrast with other Alus, e.g., AluJo and mammalian interspersed repetitive elements which have been previously associated with alternative expression. These results elucidate the role of intragenic methylation in association with alternative splicing and facilitate the evaluation of genomic variations/polymorphisms and the development of tools for the prediction of alternative splicing events
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A Predictive Model for Genomic Methylation Targets in Humans Classification of methylation-prone and resistant CpG sites through sequence analysis
2014Co-Authors: Andigoni Malousi, Sofia Kouidou, Ioanna Chouvarda, Nicos MaglaverasAbstract:DNA methylation is a tissue-specific, sequence-dependent and dynamic process, regulated by complex developmental mechanisms. Recent genome-wide studies provide compelling evidence for long-range sequence-dependence of this process, thus necessitating the computational identification of cytosine methylation and its deviations at individual CpG sites, processes which might reveal the activation of various epigenetic regulatory mechanisms. The present study deals with the prediction of methylation at single CpG sites located both in CpG islands and non-CpG islands, relying solely on the intrinsic information of the 401nt sequences centred at the candidate methylated CpG cytosines. The proposed method was evaluated on Human methylation data available by the Human Epigenome Project. The proposed Sequential Minimization Optimization classifier, when trained with the most informative features, gives highly accurate identification of the hypermethylated and hypomethylated sequences (Sn=85.35%, Sp=90.72%). Post-classification analysis of the correctly and mistakenly classified methylation targets revealed that the classification accuracy varies depending on the co-localization of the CpG sites with genomic features involved in gene expression, such as CpG islands and exonic/intronic sequences. This observation reinforces the importance of incorporating site-specific features in the predictive model and the development of site-specific classifiers. Datasets and source code are available upon request.
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DNA hypermethylation of alternatively spliced and repeat sequences in Humans
Molecular Genetics and Genomics, 2012Co-Authors: Andigoni Malousi, Sofia KouidouAbstract:DNA methylation is presently accepted as a tentative regulatory parameter in splicing. Recently, we reported significant methylation differences among various exonic splicing-enhancing elements and alternative splicing events, based on CpG methylation data from the Human Epigenome Project for chromosomes 6, 20 and 22. Presently, using a different computational approach and the same database, we report: (a) significant increase of hypermethylation in intronic and exonic sequences close to acceptor sites, relative to overall introns and exons, respectively (1,973 CpGs examined); (b) frequent CpGs, mostly hypomethylated, in donors and infrequent CpGs mostly hypermethylated, in acceptors; and (c) hypermethylation in cassette exons which are occasionally spliced and have weaker average splicing potential, relative to constitutive exons ( p
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Human Epigenome Data Reveal Increased CpG Methylation in Alternatively Spliced Sites and Putative Exonic Splicing Enhancers
DNA and cell biology, 2011Co-Authors: Christina Anastasiadou, Andigoni Malousi, Nicos Maglaveras, Sofia KouidouAbstract:The role of gene body methylation, which represents a major part of methylation in DNA, remains mostly unknown. Evidence based on the CpG distribution associates its presence with nucleosome positioning and alternative splicing. Recently, it was also shown that cytosine methylation influences splicing. However, to date, there is no methylation-based data on the association of methylation with alternative splicing and the distribution in exonic splicing enhancers (ESEs). We presently report that, based on the computational analysis of the Human Epigenome Project data, CpG hypermethylation (>80%) is frequent in alternatively spliced sites (particularly in noncanonical) but not in alternate promoters. The methylation frequency increases in sequences containing multiple putative ESEs. However, significant differences in the extent of methylation are observed among different ESEs. Specifically, moderate levels of methylation, ranging from 20% to 80%, are frequent in SRp55-binding elements, which are associated...
Andigoni Malousi - One of the best experts on this subject based on the ideXlab platform.
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ORIGINAL PAPER DNA hypermethylation of alternatively spliced and repeat sequences in Humans
2016Co-Authors: Andigoni Malousi, Sofia KouidouAbstract:Abstract DNA methylation is presently accepted as a tentative regulatory parameter in splicing. Recently, we reported significant methylation differences among various exonic splicing-enhancing elements and alternative splic-ing events, based on CpG methylation data from the Human Epigenome Project for chromosomes 6, 20 and 22. Presently, using a different computational approach and the same database, we report: (a) significant increase of hypermethylation in intronic and exonic sequences close to acceptor sites, relative to overall introns and exons, respectively (1,973 CpGs examined); (b) frequent CpGs, mostly hypomethylated, in donors and infrequent CpGs mostly hypermethylated, in acceptors; and (c) hyperme-thylation in cassette exons which are occasionally spliced and have weaker average splicing potential, relative to constitutive exons (p \ 0.0001). CpGs are hypomethylated in non-coding exons (only 16 % hypermethylation). Sin-gle-exon genes, similarly to first exons, frequently contain hypomethylated CpGs, while in internal and last exons CpGs are more frequently hypermethylated. Methylation is also more frequent in strange introns and splice sites pro-cessed by the minor spliceosome, e.g., ATAC, (p \ 0.0001 in all cases), but not in sites of incomplete processing, e.g., retained introns or bleeding exons, (p = 0.706 and p = 0.313, respectively). Most Alus, which are known to contribute to transcript presentation, are heavily methylated, in contrast with other Alus, e.g., AluJo and mammalian interspersed repetitive elements which have been previously associated with alternative expression. These results elucidate the role of intragenic methylation in association with alternative splicing and facilitate the evaluation of genomic variations/polymorphisms and the development of tools for the prediction of alternative splicing events
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A Predictive Model for Genomic Methylation Targets in Humans Classification of methylation-prone and resistant CpG sites through sequence analysis
2014Co-Authors: Andigoni Malousi, Sofia Kouidou, Ioanna Chouvarda, Nicos MaglaverasAbstract:DNA methylation is a tissue-specific, sequence-dependent and dynamic process, regulated by complex developmental mechanisms. Recent genome-wide studies provide compelling evidence for long-range sequence-dependence of this process, thus necessitating the computational identification of cytosine methylation and its deviations at individual CpG sites, processes which might reveal the activation of various epigenetic regulatory mechanisms. The present study deals with the prediction of methylation at single CpG sites located both in CpG islands and non-CpG islands, relying solely on the intrinsic information of the 401nt sequences centred at the candidate methylated CpG cytosines. The proposed method was evaluated on Human methylation data available by the Human Epigenome Project. The proposed Sequential Minimization Optimization classifier, when trained with the most informative features, gives highly accurate identification of the hypermethylated and hypomethylated sequences (Sn=85.35%, Sp=90.72%). Post-classification analysis of the correctly and mistakenly classified methylation targets revealed that the classification accuracy varies depending on the co-localization of the CpG sites with genomic features involved in gene expression, such as CpG islands and exonic/intronic sequences. This observation reinforces the importance of incorporating site-specific features in the predictive model and the development of site-specific classifiers. Datasets and source code are available upon request.
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DNA hypermethylation of alternatively spliced and repeat sequences in Humans
Molecular Genetics and Genomics, 2012Co-Authors: Andigoni Malousi, Sofia KouidouAbstract:DNA methylation is presently accepted as a tentative regulatory parameter in splicing. Recently, we reported significant methylation differences among various exonic splicing-enhancing elements and alternative splicing events, based on CpG methylation data from the Human Epigenome Project for chromosomes 6, 20 and 22. Presently, using a different computational approach and the same database, we report: (a) significant increase of hypermethylation in intronic and exonic sequences close to acceptor sites, relative to overall introns and exons, respectively (1,973 CpGs examined); (b) frequent CpGs, mostly hypomethylated, in donors and infrequent CpGs mostly hypermethylated, in acceptors; and (c) hypermethylation in cassette exons which are occasionally spliced and have weaker average splicing potential, relative to constitutive exons ( p
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Human Epigenome Data Reveal Increased CpG Methylation in Alternatively Spliced Sites and Putative Exonic Splicing Enhancers
DNA and cell biology, 2011Co-Authors: Christina Anastasiadou, Andigoni Malousi, Nicos Maglaveras, Sofia KouidouAbstract:The role of gene body methylation, which represents a major part of methylation in DNA, remains mostly unknown. Evidence based on the CpG distribution associates its presence with nucleosome positioning and alternative splicing. Recently, it was also shown that cytosine methylation influences splicing. However, to date, there is no methylation-based data on the association of methylation with alternative splicing and the distribution in exonic splicing enhancers (ESEs). We presently report that, based on the computational analysis of the Human Epigenome Project data, CpG hypermethylation (>80%) is frequent in alternatively spliced sites (particularly in noncanonical) but not in alternate promoters. The methylation frequency increases in sequences containing multiple putative ESEs. However, significant differences in the extent of methylation are observed among different ESEs. Specifically, moderate levels of methylation, ranging from 20% to 80%, are frequent in SRp55-binding elements, which are associated...
Susan J. Clark - One of the best experts on this subject based on the ideXlab platform.
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Moving AHEAD with an international Human Epigenome Project
Nature, 2008Co-Authors: Peter A. Jones, Stephan Beck, Trevor K. Archer, Stephen B. Baylin, Shelley L. Berger, Bradley E. Bernstein, John D. Carpten, Susan J. Clark, Joseph F. Costello, Rebecca W. DoergeAbstract:A plan to 'genomicize' epigenomics research and pave the way for breakthroughs in the prevention, diagnosis and treatment of Human disease.
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Genomic profiling of CpG methylation and allelic specificity using quantitative high-throughput mass spectrometry: critical evaluation and improvements
Nucleic acids research, 2007Co-Authors: Marcel W. Coolen, Aaron L. Statham, Margaret Gardiner-garden, Susan J. ClarkAbstract:CpG methylation is a key component of the Epigenome architecture that is associated with changes in gene expression without a change to the DNA sequence. Since the first reports on deregulation of DNA methylation, in diseases such as cancer, and the initiation of the Human Epigenome Project, an increasing need has arisen for a detailed, high-throughput and quantitative method of analysis to discover and validate normal and aberrant DNA methylation profiles in large sample cohorts. Here we present an improved protocol using base-specific fragmentation and MALDI-TOF mass spectrometry that enables a sensitive and high-throughput method of DNA methylation analysis, quantitative to 5% methylation for each informative CpG residue. We have determined the accuracy, variability and sensitivity of the protocol, implemented critical improvements in experimental design and interpretation of the data and developed a new formula to accurately measure CpG methylation. Key innovations now permit determination of differential and allele-specific methylation, such as in cancer and imprinting. The new protocol is ideally suitable for detailed DNA methylation analysis of multiple genomic regions and large sample cohorts that is critical for comprehensive profiling of normal and diseased Human Epigenomes.
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Action at a distance: epigenetic silencing of large chromosomal regions in carcinogenesis
Human Molecular Genetics, 2007Co-Authors: Susan J. ClarkAbstract:Despite the completion of the Human Genome Project, we are still far from understanding the molecular events underlying epigenetic change in cancer. Cancer is a disease of the DNA with both genetic and epigenetic changes contributing to changes in gene expression. Epigenetics involves the interplay between DNA methylation, histone modifications and expression of non-coding RNAs in the regulation of gene transcription. We now know that tumour suppressor genes, with CpG island-associated promoters, are commonly hypermethylated and silenced in cancer, but we do not understood what triggers this process or when it occurs during carcinogenesis. Epigenetic gene silencing has always been envisaged as a local event silencing discrete genes, but recent data now indicates that large regions of chromosomes can be co-coordinately suppressed; a process termed long range epigenetic silencing (LRES). LRES can span megabases of DNA and involves broad heterochromatin formation accompanied by hypermethylation of clusters of contiguous CpG islands within the region. It is not clear if LRES is initiated by one critical gene target that spreads and conscripts innocent bystanders, analogous to large genetic deletions or if coordinate silencing of multiple genes is important in carcinogenesis? Over the next decade with the exciting new genomic approaches to Epigenome analysis and the initiation of a Human Epigenome Project, we will understand more about the interplay between DNA methylation and chromatin modifications and the expression of non-coding RNAs, promising a new range of molecular diagnostic cancer markers and molecular targets for cancer epigenetic therapy.
Alexander Olek - One of the best experts on this subject based on the ideXlab platform.
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DNA Methylation Profiling of the Human Major Histocompatibility Complex: A Pilot Study for the Human Epigenome Project
PLoS biology, 2004Co-Authors: Vardhman K. Rakyan, Thomas Hildmann, K L Novik, Jörn Lewin, Jörg Tost, Antony V. Cox, T. Dan Andrews, Kevin L. Howe, Thomas J. Otto, Alexander OlekAbstract:The Human Epigenome Project aims to identify, catalogue, and interpret genome-wide DNA methylation phenomena. Occurring naturally on cytosine bases at cytosine-guanine dinucleotides, DNA methylation is intimately involved in diverse biological processes and the aetiology of many diseases. Differentially methylated cytosines give rise to distinct profiles, thought to be specific for gene activity, tissue type, and disease state. The identification of such methylation variable positions will significantly improve our understanding of genome biology and our ability to diagnose disease. Here, we report the results of the pilot study for the Human Epigenome Project entailing the methylation analysis of the Human major histocompatibility complex. This study involved the development of an integrated pipeline for high-throughput methylation analysis using bisulphite DNA sequencing, discovery of methylation variable positions, epigenotyping by matrix-assisted laser desorption/ionisation mass spectrometry, and development of an integrated public database available at http://www.Epigenome.org. Our analysis of DNA methylation levels within the major histocompatibility complex, including regulatory exonic and intronic regions associated with 90 genes in multiple tissues and individuals, reveals a bimodal distribution of methylation profiles (i.e., the vast majority of the analysed regions were either hypo- or hypermethylated), tissue specificity, inter-individual variation, and correlation with independent gene expression data.
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Epigenomics: genome-wide study of methylation phenomena.
Current issues in molecular biology, 2002Co-Authors: K L Novik, Alexander Olek, I Nimmrich, B Genc, S Maier, C. Piepenbrock, Stephan BeckAbstract:Epigenetics is one of the key areas of future research that can elucidate how genomes work. It combines genetics and the environment to address complex biological systems such as the plasticity of our genome. While all nucleated Human cells carry the same genome, they express different genes at different times. Much of this is governed by epigenetic changes resulting in differential methylation of our genome--or different Epigenomes. Individual studies over the past decades have already established the involvement of DNA methylation in imprinting, gene regulation, chromatin structure, genome stability and disease, especially cancer. Now, in the wake of the Human Genome Project (HGP), epigenetic phenomena can be studied genome-wide and are giving rise to a new field, epigenomics. Here, we review the current and future potential of this field and introduce the pilot study towards the Human Epigenome Project (HEP).