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1. Epigenomic annotation of noncoding mutations identifies mutated pathways in primary liver cancer.

Author

Rebecca F Lowdon and Ting Wang

Subjects
Medicine, Science
Abstract

Evidence that noncoding mutation can result in cancer driver events is mounting. However, it is more difficult to assign molecular biological consequences to noncoding mutations than to coding mutations, and a typical cancer genome contains many more noncoding mutations than protein-coding mutations. Accordingly, parsing functional noncoding mutation signal from noise remains an important challenge. Here we use an empirical approach to identify putatively functional noncoding somatic single nucleotide variants (SNVs) from liver cancer genomes. Annotation of candidate variants by publicly available epigenome datasets finds that 40.5% of SNVs fall in regulatory elements. When assigned to specific regulatory elements, we find that the distribution of regulatory element mutation mirrors that of nonsynonymous coding mutation, where few regulatory elements are recurrently mutated in a patient population but many are singly mutated. We find potential gain-of-binding site events among candidate SNVs, suggesting a mechanism of action for these variants. When aggregating noncoding somatic mutation in promoters, we find that genes in the ERBB signaling and MAPK signaling pathways are significantly enriched for promoter mutations. Altogether, our results suggest that functional somatic SNVs in cancer are sporadic, but occasionally occur in regulatory elements and may affect phenotype by creating binding sites for transcriptional regulators. Accordingly, we propose that noncoding mutation should be formally accounted for when determining gene- and pathway-mutation burden in cancer.

Published
2017
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2. Epigenetic dynamics shaping melanophore and iridophore cell fate in zebrafish

Author

Hyo Sik Jang, Yujie Chen, Jiaxin Ge, Alicia N. Wilkening, Yiran Hou, Hyung Joo Lee, You Rim Choi, Rebecca F. Lowdon, Xiaoyun Xing, Daofeng Li, Charles K. Kaufman, Stephen L. Johnson, and Ting Wang

Subjects
Biology (General), QH301-705.5, Genetics, QH426-470
Abstract

Abstract Background Zebrafish pigment cell differentiation provides an attractive model for studying cell fate progression as a neural crest progenitor engenders diverse cell types, including two morphologically distinct pigment cells: black melanophores and reflective iridophores. Nontrivial classical genetic and transcriptomic approaches have revealed essential molecular mechanisms and gene regulatory circuits that drive neural crest-derived cell fate decisions. However, how the epigenetic landscape contributes to pigment cell differentiation, especially in the context of iridophore cell fate, is poorly understood. Results We chart the global changes in the epigenetic landscape, including DNA methylation and chromatin accessibility, during neural crest differentiation into melanophores and iridophores to identify epigenetic determinants shaping cell type-specific gene expression. Motif enrichment in the epigenetically dynamic regions reveals putative transcription factors that might be responsible for driving pigment cell identity. Through this effort, in the relatively uncharacterized iridophores, we validate alx4a as a necessary and sufficient transcription factor for iridophore differentiation and present evidence on alx4a’s potential regulatory role in guanine synthesis pathway. Conclusions Pigment cell fate is marked by substantial DNA demethylation events coupled with dynamic chromatin accessibility to potentiate gene regulation through cis-regulatory control. Here, we provide a multi-omic resource for neural crest differentiation into melanophores and iridophores. This work led to the discovery and validation of iridophore-specific alx4a transcription factor.

Published
2021
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3. Integrative analysis of 111 reference human epigenomes Open.

Author

Roadmap Epigenomics Consortium, Anshul Kundaje, Wouter Meuleman, Jason Ernst, Misha Bilenky, Angela Yen, Alireza Heravi Moussavi, Pouya Kheradpour, ZhiZhuo Zhang, Jianrong Wang, Michael J. Ziller, Viren Amin, John W. Whitaker, Matthew D. Schultz, Lucas D. Ward, Abhishek Sarkar, Gerald T. Quon, Richard S. Sandstrom, Matthew L. Eaton, Yi-Chieh Wu, Andreas R. Pfenning, Xinchen Wang, Melina Claussnitzer, Yaping Liu, Cristian Coarfa, R. Alan Harris, Noam Shoresh, Charles B. Epstein, Elizabeta Gjoneska, Danny Leung, Wei Xie, R. David Hawkins, Ryan Lister, Chibo Hong, Philippe Gascard, Andrew J. Mungall, Richard A. Moore, Eric Chuah, Angela Tam, Theresa K. Canfield, R. Scott Hansen, Rajinder Kaul, Peter J. Sabo, Mukul S. Bansal, Annaick Carles, Jesse R. Dixon, Kyle Kai-How Farh, Soheil Feizi, Rosa Karlic, Ah-Ram Kim, Ashwinikumar Kulkarni, Daofeng Li, Rebecca F. Lowdon, GiNell Elliott, Tim R. Mercer, Shane J. Neph, Vitor Onuchic, Paz Polak, Nisha Rajagopal, Pradipta Ray, Richard C. Sallari, Kyle T. Siebenthall, Nicholas A. Sinnott-Armstrong, Michael Stevens, Robert E. Thurman, Jie Wu, Bo Zhang 0009, Xin Zhou, Arthur E. Beaudet, Laurie A. Boyer, Philip L. De Jager, Peggy J. Farnham, Susan J. Fisher, David Haussler, Steven J. M. Jones, Wei Li, Marco A. Marra, Michael T. McManus, Shamil R. Sunyaev, James A. Thomson, Thea D. Tlsty, Li-Huei Tsai, Wei Wang 0051, Robert A. Waterland, Michael Q. Zhang, Lisa H. Chadwick, Bradley E. Bernstein, Joseph F. Costello, Joseph R. Ecker, Martin Hirst, Alexander Meissner, Aleksandar Milosavljevic, Bing Ren, John A. Stamatoyannopoulos, Ting Wang, and Manolis Kellis

Published
2015
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4. Epigenetic dynamics shaping melanophore and iridophore cell fate in zebrafish

Author

You Rim Choi, Charles K. Kaufman, Daofeng Li, Ting Wang, Hyo Sik Jang, Jiaxin Ge, Rebecca F. Lowdon, Stephen L. Johnson, Alicia N Wilkening, Yiran Hou, Yujie Chen, Hyung Joo Lee, and Xiaoyun Xing

Subjects
Transcription, Genetic, QH301-705.5, Melanophores, Regulatory Sequences, Nucleic Acid, Cell fate determination, QH426-470, Iridophore differentiation, Epigenesis, Genetic, Pigment cell differentiation, Melanophore, Genetics, Animals, Gene Regulatory Networks, Chromatophores, Epigenetics, Biology (General), Transcription factor, Zebrafish, biology, Research, Cell Differentiation, DNA Methylation, Zebrafish Proteins, biology.organism_classification, Chromatin, Cell biology, Neural Crest, CpG Islands, Transcription Factors
Abstract

BackgroundZebrafish pigment cell differentiation provides an attractive model for studying cell fate progression as a neural crest progenitor engenders diverse cell types, including two morphologically distinct pigment cells: black melanophores and reflective iridophores. Nontrivial classical genetic and transcriptomic approaches have revealed essential molecular mechanisms and gene regulatory circuits that drive neural crest-derived cell fate decisions. However, how the epigenetic landscape contributes to pigment cell differentiation, especially in the context of iridophore cell fate, is poorly understood.ResultsWe chart the global changes in the epigenetic landscape, including DNA methylation and chromatin accessibility, during neural crest differentiation into melanophores and iridophores to identify epigenetic determinants shaping cell type-specific gene expression. Motif enrichment in the epigenetically dynamic regions reveals putative transcription factors that might be responsible for driving pigment cell identity. Through this effort, in the relatively uncharacterized iridophores, we validatealx4aas a necessary and sufficient transcription factor for iridophore differentiation and present evidence onalx4a’s potential regulatory role in guanine synthesis pathway.ConclusionsPigment cell fate is marked by substantial DNA demethylation events coupled with dynamic chromatin accessibility to potentiate gene regulation through cis-regulatory control. Here, we provide a multi-omic resource for neural crest differentiation into melanophores and iridophores. This work led to the discovery and validation of iridophore-specificalx4atranscription factor.

Published
2021

6. Human placental cytotrophoblast epigenome dynamics over gestation and alterations in placental disease

Author

Bo Zhang, Renee L. Sears, Susan J. Fisher, Martin Hirst, Guangfeng Zhao, Joshua F. Robinson, Michael T. McMaster, Ting Wang, Joseph F. Costello, Steven J.M. Jones, Marco A. Marra, M. Yvonne Kim, Gi Nell Elliot, Mirhan Kapidzic, Rebecca F. Lowdon, Emily G. Hamilton, Yan Zhou, Chibo Hong, Matthew Gormley, Tali Mazor, Erica C. Pehrsson, Misha Bilenky, and Daofeng Li

Subjects
Placenta Diseases, cytotrophoblast, Reproductive health and childbirth, Medical and Health Sciences, H3K9me3, Histones, Transcriptome, Epigenome, human placenta, 0302 clinical medicine, Pre-Eclampsia, Pregnancy, 2.1 Biological and endogenous factors, Developmental, histone modification, Aetiology, reproductive and urinary physiology, Pediatric, 0303 health sciences, DNA methylation, biology, Gene Expression Regulation, Developmental, Acetylation, chorionic villi, Biological Sciences, H3K27ac, Trophoblasts, Enhancer Elements, Genetic, Histone, medicine.anatomical_structure, embryonic structures, Female, Cytotrophoblasts, Biotechnology, gestational regulation, Pediatric Research Initiative, Enhancer Elements, 1.1 Normal biological development and functioning, Gestational Age, General Biochemistry, Genetics and Molecular Biology, Preeclampsia, preeclampsia, Andrology, 03 medical and health sciences, Genetic, Clinical Research, Underpinning research, Genetics, medicine, Humans, Molecular Biology, Protein Processing, 030304 developmental biology, Cytotrophoblast, Lysine, Contraception/Reproduction, Human Genome, Post-Translational, Cell Biology, DNA Methylation, Placental disease, medicine.disease, Good Health and Well Being, Gene Expression Regulation, biology.protein, placental disease, Protein Processing, Post-Translational, 030217 neurology & neurosurgery, Developmental Biology
Abstract

The human placenta and its specialized cytotrophoblasts rapidly develop, have a compressed lifespan, govern pregnancy outcomes, and program the offspring's health. Understanding the molecular underpinnings of these behaviors informs development and disease. Profiling the extraembryonic epigenome and transcriptome during the 2nd and 3rd trimesters revealed H3K9 trimethylation overlapping deeply DNA hypomethylated domains with reduced gene expression and compartment-specific patterns that illuminated their functions. Cytotrophoblast DNA methylation increased, and several key histone modifications decreased across the genome as pregnancy advanced. Cytotrophoblasts from severe preeclampsia had substantially increased H3K27 acetylation globally and at genes that are normally downregulated at term but upregulated in this syndrome. In addition, some cases had an immature pattern of H3K27ac peaks, and others showed evidence of accelerated aging, suggesting subtype-specific alterations in severe preeclampsia. Thus, the cytotrophoblast epigenome dramatically reprograms during pregnancy, placental disease is associated with failures in this process, and H3K27 hyperacetylation is a feature of severe preeclampsia.

Published
2021

7. Tissue-specific DNA methylation is conserved across human, mouse, and rat, and driven by primary sequence conservation

Author

Ting Wang, Theodore J. Cicero, Daofeng Li, Rebecca F. Lowdon, Hyung Joo Lee, Jia Zhou, Nicole B. Rockweiler, Mayank N. K. Choudhary, Hyo Sik Jang, C. Charles Gu, Bo Zhang, Renee L. Sears, Xiaoyun Xing, Brianne Tabers, and Jason Arand

Subjects
Epigenomics, 0301 basic medicine, lcsh:QH426-470, lcsh:Biotechnology, Biology, Evolution, Molecular, Mice, 03 medical and health sciences, lcsh:TP248.13-248.65, Genetics, Animals, Humans, Epigenetics, Conserved Sequence, Binding Sites, DNA methylation, Comparative epigenomics, Tissue-specific, Comparative genomics, Methylation, Epigenome, Epigenetic conservation, Rats, DNA binding site, lcsh:Genetics, 030104 developmental biology, Differentially methylated regions, Histone, Organ Specificity, biology.protein, Transcription Factors, Research Article, Biotechnology
Abstract

Background Uncovering mechanisms of epigenome evolution is an essential step towards understanding the evolution of different cellular phenotypes. While studies have confirmed DNA methylation as a conserved epigenetic mechanism in mammalian development, little is known about the conservation of tissue-specific genome-wide DNA methylation patterns. Results Using a comparative epigenomics approach, we identified and compared the tissue-specific DNA methylation patterns of rat against those of mouse and human across three shared tissue types. We confirmed that tissue-specific differentially methylated regions are strongly associated with tissue-specific regulatory elements. Comparisons between species revealed that at a minimum 11-37% of tissue-specific DNA methylation patterns are conserved, a phenomenon that we define as epigenetic conservation. Conserved DNA methylation is accompanied by conservation of other epigenetic marks including histone modifications. Although a significant amount of locus-specific methylation is epigenetically conserved, the majority of tissue-specific DNA methylation is not conserved across the species and tissue types that we investigated. Examination of the genetic underpinning of epigenetic conservation suggests that primary sequence conservation is a driving force behind epigenetic conservation. In contrast, evolutionary dynamics of tissue-specific DNA methylation are best explained by the maintenance or turnover of binding sites for important transcription factors. Conclusions Our study extends the limited literature of comparative epigenomics and suggests a new paradigm for epigenetic conservation without genetic conservation through analysis of transcription factor binding sites. Electronic supplementary material The online version of this article (10.1186/s12864-017-4115-6) contains supplementary material, which is available to authorized users.

Published
2017

8. Evolution of Epigenetic Regulation in Vertebrate Genomes

Author

Ting Wang, Rebecca F. Lowdon, and Hyo Sik Jang

Subjects
0301 basic medicine, Genomics, Biology, Genome, Article, Evolution, Molecular, 03 medical and health sciences, 0302 clinical medicine, Phylogenetics, Genetics, Animals, Humans, Epigenetics, Phylogeny, Epigenomics, Mechanism (biology), Human evolutionary genetics, Computational Biology, Epigenome, 030104 developmental biology, Evolutionary biology, Vertebrates, Algorithms, 030217 neurology & neurosurgery
Abstract

Empirical models of sequence evolution have spurred progress in the field of evolutionary genetics for decades. We are now realizing the importance and complexity of the eukaryotic epigenome. While epigenome analysis has been applied to genomes from single-cell eukaryotes to human, comparative analyses are still relatively few and computational algorithms to quantify epigenome evolution remain scarce. Accordingly, a quantitative model of epigenome evolution remains to be established. We review here the comparative epigenomics literature and synthesize its overarching themes. We also suggest one mechanism, transcription factor binding site (TFBS) turnover, which relates sequence evolution to epigenetic conservation or divergence. Lastly, we propose a framework for how the field can move forward to build a coherent quantitative model of epigenome evolution.

Published
2016

9. Functional DNA methylation differences between tissues, cell types, and across individuals discovered using the M&M algorithm

Author

Ginell Elliott, Taoping Shi, Junchen Gu, Marco A. Marra, Philippe Gascard, Yan Zhou, Xiaoyun Xing, Daofeng Li, Chibo Hong, Angela Tam, Joseph F. Costello, Ting Wang, Pamela A. F. Madden, Nan Lin, Bo Zhang, Hyung Joo Lee, Michael Stevens, Peggy J. Farnham, Theresa A. Kadlecek, Henriette O'Geen, Baoxue Zhang, Arthur Weiss, Jia Zhou, Thea D. Tlsty, Martin Hirst, Vasavi Sundaram, Richard A. Moore, Raman P. Nagarajan, Keith L. Ligon, Jeffrey B. Cheng, Mahvash Sigaroudinia, Cecile L. Maire, and Rebecca F. Lowdon

Subjects
Genetics, Genome, Human, genetic processes, Bisulfite sequencing, Method, High-Throughput Nucleotide Sequencing, Sequence Analysis, DNA, DNA Methylation, Biology, Differentially methylated regions, Organ Specificity, Data Interpretation, Statistical, DNA methylation, Humans, Illumina Methylation Assay, natural sciences, Methylated DNA immunoprecipitation, Epigenetics, RNA-Directed DNA Methylation, Algorithms, Genetics (clinical), Epigenomics
Abstract

DNA methylation plays key roles in diverse biological processes such as X chromosome inactivation, transposable element repression, genomic imprinting, and tissue-specific gene expression. Sequencing-based DNA methylation profiling provides an unprecedented opportunity to map and compare complete DNA methylomes. This includes one of the most widely applied technologies for measuring DNA methylation: methylated DNA immunoprecipitation followed by sequencing (MeDIP-seq), coupled with a complementary method, methylation-sensitive restriction enzyme sequencing (MRE-seq). A computational approach that integrates data from these two different but complementary assays and predicts methylation differences between samples has been unavailable. Here, we present a novel integrative statistical framework M&M (for integration of MeDIP-seq and MRE-seq) that dynamically scales, normalizes, and combines MeDIP-seq and MRE-seq data to detect differentially methylated regions. Using sample-matched whole-genome bisulfite sequencing (WGBS) as a gold standard, we demonstrate superior accuracy and reproducibility of M&M compared to existing analytical methods for MeDIP-seq data alone. M&M leverages the complementary nature of MeDIP-seq and MRE-seq data to allow rapid comparative analysis between whole methylomes at a fraction of the cost of WGBS. Comprehensive analysis of nineteen human DNA methylomes with M&M reveals distinct DNA methylation patterns among different tissue types, cell types, and individuals, potentially underscoring divergent epigenetic regulation at different scales of phenotypic diversity. We find that differential DNA methylation at enhancer elements, with concurrent changes in histone modifications and transcription factor binding, is common at the cell, tissue, and individual levels, whereas promoter methylation is more prominent in reinforcing fundamental tissue identities.

Published
2013

10. DNA hypomethylation within specific transposable element families associates with tissue-specific enhancer landscape

Author

Peggy J. Farnham, Stephanie Cho, Mingchao Xie, Ting Wang, Joseph F. Costello, Baljit Kamoh, Marco A. Marra, Thea D. Tlsty, Martin Hirst, Angela Tam, Pamela A. F. Madden, Andrew J. Mungall, Xin Zhou, Cecile L. Maire, Bo Zhang, Hyung Joo Lee, Richard A. Moore, Arthur Weiss, Keith L. Ligon, Philippe Gascard, Chibo Hong, Henriette O'Geen, Xiaoyun Xing, Theresa A. Kadlecek, Daofeng Li, Mahvash Sigaroudinia, and Rebecca F. Lowdon

Subjects
Adult, Transposable element, Biology, Genome, Article, Epigenesis, Genetic, Histones, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Genetics, Humans, Enhancer, Cells, Cultured, 030304 developmental biology, Epigenomics, 0303 health sciences, Binding Sites, Genome, Human, Chromosome Mapping, DNA Methylation, Embryo, Mammalian, Enhancer Elements, Genetic, chemistry, Organ Specificity, Multigene Family, DNA methylation, DNA Transposable Elements, Human genome, 030217 neurology & neurosurgery, DNA, DNA hypomethylation
Abstract

Transposable element (TE)-derived sequences comprise half of the human genome and DNA methylome and are presumed to be densely methylated and inactive. Examination of genome-wide DNA methylation status within 928 TE subfamilies in human embryonic and adult tissues identified unexpected tissue-specific and subfamily-specific hypomethylation signatures. Genes proximal to tissue-specific hypomethylated TE sequences were enriched for functions important for the relevant tissue type, and their expression correlated strongly with hypomethylation within the TEs. When hypomethylated, these TE sequences gained tissue-specific enhancer marks, including monomethylation of histone H3 at lysine 4 (H3K4me1) and occupancy by p300, and a majority exhibited enhancer activity in reporter gene assays. Many such TEs also harbored binding sites for transcription factors that are important for tissue-specific functions and showed evidence of evolutionary selection. These data suggest that sequences derived from TEs may be responsible for wiring tissue type-specific regulatory networks and may have acquired tissue-specific epigenetic regulation.

Published
2013

11. Integrative Analysis of the Caenorhabditis elegans Genome by the modENCODE Project

Author

L. Dick, Mark S. Guyer, D. Mecenas, William C. Spencer, Ming Sin Cheung, Sebastian D. Mackowiak, Tao Liu, A. Vielle, Abby F. Dernburg, Mitzi Morris, Bradley I. Arshinoff, Sheldon J. McKay, Amber Leahey, Thea A. Egelhofer, Lukas Habegger, Michael Snyder, Teruaki Takasaki, Roger P. Alexander, Stuart K. Kim, Ashish Agarwal, Ting Han, A. Leo Iniguez, Eric L. Van Nostrand, Gos Micklem, S. Taing, Ekta Khurana, Joel Rozowsky, Beijing Wu, Steven Henikoff, Adrian Carr, Philip Green, Angie S. Hinrichs, A. Muroyama, Jason D. Lieb, Paul Lloyd, Yaniv Lubling, P. Scheid, Kevin Y. Yip, Stefan R. Henz, Chao Cheng, Jiang Du, Mei Zhong, P. Alves, Elicia Preston, Zhi John Lu, Vishal Khivansara, Robert H. Waterston, J. Janette, C. Slightam, Frank J. Slack, David M. Miller, Eo Stinson, Nikolaus Rajewsky, Eran Segal, Jing Leng, Tony Hyman, R. Robilotto, C. Shou, Gunnar Rätsch, Eric C. Lai, Mihail Sarov, X. Shirley Liu, Isabel J. Latorre, A. Chateigner, Francois Gullier, Raymond K. Auerbach, W. James Kent, Sergio Contrino, Jeremy Brouillet, Lincoln Stein, T. Phippen, Andrea Sboner, Marco Mangone, Georg Zeller, Hoang Pham, Mark Gerstein, Michael J. MacCoss, Siew Loon Ooi, Cathleen M. Brdlik, D. Vafeados, Nicole L. Washington, Andreas Rechtsteiner, Peter J. Good, Susan Strome, Galt P. Barber, Kristin C. Gunsalus, John I. Murray, Valerie Reinke, Luke Dannenberg, Masaomi Kato, M. Jensen, X. Feng, John Kim, Kahn Rhrissorrakrai, H. Holster, Kohta Ikegami, Christina M. Whittle, M. Gutwein, Rachel Lyne, Wei Niu, Richard J.H. Smith, LaDeana W. Hillier, P. Kolasinska-Zwierz, Heidi Rosenbaum, Andréa C. Dosé, Xingliang Zhou, Marc D. Perry, Rajkumar Sasidharan, Rebecca F. Lowdon, Arshad Desai, Z. Zha, J. Brennan, Guilin Wang, P. Ruzanov, Brent Ewing, Gennifer E. Merrihew, Kim Rutherford, Reto Gassmann, Elise A. Feingold, Fabio Piano, Julie Ahringer, E. Kephart, Lucas Lochovsky, Sevinc Ercan, Suzanna E. Lewis, Ksenia Voronina, Koon-Kiu Yan, Jorja G. Henikoff, Hyunjin Shin, Hiram Clawson, and Ghia Euskirchen

Subjects
Gene expression profiling, Genetics, Multidisciplinary, biology, Chromosome, Genomics, Genome project, biology.organism_classification, Gene, Genome, Caenorhabditis elegans, Chromatin
Abstract

From Genome to Regulatory Networks For biologists, having a genome in hand is only the beginning—much more investigation is still needed to characterize how the genome is used to help to produce a functional organism (see the Perspective by Blaxter ). In this vein, Gerstein et al. (p. 1775 ) summarize for the Caenorhabditis elegans genome, and The modENCODE Consortium (p. 1787 ) summarize for the Drosophila melanogaster genome, full transcriptome analyses over developmental stages, genome-wide identification of transcription factor binding sites, and high-resolution maps of chromatin organization. Both studies identified regions of the nematode and fly genomes that show highly occupied targets (or HOT) regions where DNA was bound by more than 15 of the transcription factors analyzed and the expression of related genes were characterized. Overall, the studies provide insights into the organization, structure, and function of the two genomes and provide basic information needed to guide and correlate both focused and genome-wide studies.

Published
2010

12. Developmental enhancers revealed by extensive DNA methylome maps of zebrafish early embryos

Author

Michael Stevens, Stephen L. Johnson, Ting Wang, Daofeng Li, Rebecca F. Lowdon, Bo Zhang, Brett B Maricque, and Hyung Joo Lee

Subjects
Male, Green Fluorescent Proteins, Embryonic Development, General Physics and Astronomy, Article, General Biochemistry, Genetics and Molecular Biology, Epigenesis, Genetic, Histones, Animals, Gene Regulatory Networks, Promoter Regions, Genetic, Enhancer, Zebrafish, Gene Library, Genetics, Regulation of gene expression, Multidisciplinary, biology, Gene Expression Regulation, Developmental, DNA, Sequence Analysis, DNA, General Chemistry, Methylation, DNA Methylation, biology.organism_classification, Enhancer Elements, Genetic, Histone, Differentially methylated regions, CpG site, DNA methylation, biology.protein, CpG Islands, Female, Signal Transduction
Abstract

DNA methylation undergoes dynamic changes during development and cell differentiation. Recent genome-wide studies discovered that tissue-specific differentially methylated regions (DMRs) often overlap tissue-specific distal cis-regulatory elements. However, developmental DNA methylation dynamics of the majority of the genomic CpGs outside gene promoters and CpG islands has not been extensively characterized. Here, we generate and compare comprehensive DNA methylome maps of zebrafish developing embryos. From these maps, we identify thousands of developmental stage-specific DMRs (dsDMRs) across zebrafish developmental stages. The dsDMRs contain evolutionarily conserved sequences, are associated with developmental genes and are marked with active enhancer histone posttranslational modifications. Their methylation pattern correlates much stronger than promoter methylation with expression of putative target genes. When tested in vivo using a transgenic zebrafish assay, 20 out of 20 selected candidate dsDMRs exhibit functional enhancer activities. Our data suggest that developmental enhancers are a major target of DNA methylation changes during embryogenesis.

Published
2015

13. Epigenomic annotation of genetic variants using the Roadmap Epigenome Browser

Author

Daofeng Li, Nicole B. Rockweiler, Rebecca F. Lowdon, Pamela A. F. Madden, Bo Zhang, Ting Wang, Ivan Smirnov, Joseph F. Costello, Xin Zhou, and Renee L. Sears

Subjects
Web browser, Genome, Human, Biomedical Engineering, Genetic variants, Chromosome Mapping, Genetic Variation, Bioengineering, Computational biology, Epigenome, Biology, Web Browser, Applied Microbiology and Biotechnology, Genome, Polymorphism, Single Nucleotide, Human genetics, Article, Epigenesis, Genetic, Annotation, User-Computer Interface, Databases, Genetic, Molecular Medicine, Database Management Systems, Humans, Biotechnology, Epigenomics
Published
2015

14. Regulatory network decoded from epigenomes of surface ectoderm-derived cell types

Author

Peggy J. Farnham, Joseph F. Costello, Bo Zhang, Jeffrey B. Cheng, Daofeng Li, T. Mauro, Mahvash Sigaroudinia, Thea D. Tlsty, Martin Hirst, Rebecca F. Lowdon, Ting Wang, Misha Bilenky, Boris C. Bastian, Philippe Gascard, and Marco A. Marra

Subjects
Keratinocytes, Cell type, Cellular differentiation, General Physics and Astronomy, Ectoderm, Biology, Article, General Biochemistry, Genetics and Molecular Biology, Epigenesis, Genetic, 03 medical and health sciences, 0302 clinical medicine, Species Specificity, medicine, Humans, Gene Regulatory Networks, Promoter Regions, Genetic, Cells, Cultured, 030304 developmental biology, Epigenomics, Genetics, 0303 health sciences, Multidisciplinary, Myoepithelial cell, Cell Differentiation, General Chemistry, DNA Methylation, Fibroblasts, Surface ectoderm, Differentially methylated regions, medicine.anatomical_structure, 030220 oncology & carcinogenesis, DNA methylation, Melanocytes
Abstract

Developmental history shapes the epigenome and biological function of differentiated cells. Epigenomic patterns have been broadly attributed to the three embryonic germ layers. Here we investigate how developmental origin influences epigenomes. We compare key epigenomes of cell types derived from surface ectoderm (SE), including keratinocytes and breast luminal and myoepithelial cells, against neural crest-derived melanocytes and mesoderm-derived dermal fibroblasts, to identify SE differentially methylated regions (SE-DMRs). DNA methylomes of neonatal keratinocytes share many more DMRs with adult breast luminal and myoepithelial cells than with melanocytes and fibroblasts from the same neonatal skin. This suggests that SE origin contributes to DNA methylation patterning, while shared skin tissue environment has limited effect on epidermal keratinocytes. Hypomethylated SE-DMRs are in proximity to genes with SE relevant functions. They are also enriched for enhancer- and promoter-associated histone modifications in SE-derived cells, and for binding motifs of transcription factors important in keratinocyte and mammary gland biology. Thus, epigenomic analysis of cell types with common developmental origin reveals an epigenetic signature that underlies a shared gene regulatory network.

Published
2014

15. Comparative DNA methylome analysis of endometrial carcinoma reveals complex and distinct deregulation of cancer promoters and enhancers

Author

Bo Zhang, Ting Wang, Xiao Yun Xing, Jing Li, Katherine B. Chiappinelli, Paul J. Goodfellow, David G. Mutch, Rebecca F. Lowdon, Nan Lin, Vasavi Sundaram, Ian S. Hagemann, Baoxue Zhang, and Yan Zhou

Subjects
Kruppel-Like Transcription Factors, Biology, Polymorphism, Single Nucleotide, Aldehyde Dehydrogenase 1 Family, Kruppel-Like Factor 4, Genetics, Humans, DNA (Cytosine-5-)-Methyltransferases, Methylated DNA immunoprecipitation, Promoter Regions, Genetic, Enhancer, Adaptor Proteins, Signal Transducing, Chromosomes, Human, X, Nuclear Proteins, Retinal Dehydrogenase, Promoter, Sequence Analysis, DNA, Methylation, DNA Methylation, Molecular biology, Carcinoma, Papillary, Endometrial Neoplasms, 3. Good health, Enhancer Elements, Genetic, Differentially methylated regions, CpG site, Uterine Neoplasms, DNA methylation, DNA Transposable Elements, CpG Islands, Female, RNA, Long Noncoding, DNA microarray, MutL Protein Homolog 1, Research Article, Biotechnology
Abstract

Background Aberrant DNA methylation is a hallmark of many cancers. Classically there are two types of endometrial cancer, endometrioid adenocarcinoma (EAC), or Type I, and uterine papillary serous carcinoma (UPSC), or Type II. However, the whole genome DNA methylation changes in these two classical types of endometrial cancer is still unknown. Results Here we described complete genome-wide DNA methylome maps of EAC, UPSC, and normal endometrium by applying a combined strategy of methylated DNA immunoprecipitation sequencing (MeDIP-seq) and methylation-sensitive restriction enzyme digestion sequencing (MRE-seq). We discovered distinct genome-wide DNA methylation patterns in EAC and UPSC: 27,009 and 15,676 recurrent differentially methylated regions (DMRs) were identified respectively, compared with normal endometrium. Over 80% of DMRs were in intergenic and intronic regions. The majority of these DMRs were not interrogated on the commonly used Infinium 450K array platform. Large-scale demethylation of chromosome X was detected in UPSC, accompanied by decreased XIST expression. Importantly, we discovered that the majority of the DMRs harbored promoter or enhancer functions and are specifically associated with genes related to uterine development and disease. Among these, abnormal methylation of transposable elements (TEs) may provide a novel mechanism to deregulate normal endometrium-specific enhancers derived from specific TEs. Conclusions DNA methylation changes are an important signature of endometrial cancer and regulate gene expression by affecting not only proximal promoters but also distal enhancers. Electronic supplementary material The online version of this article (doi:10.1186/1471-2164-15-868) contains supplementary material, which is available to authorized users.

Published
2014

16. Integrative analysis of 111 reference human epigenomes

Author

Daofeng Li, Tim R. Mercer, Wei Li, Lisa Helbling Chadwick, Jesse R. Dixon, Pouya Kheradpour, Joseph F. Costello, Pradipta R. Ray, John W. Whitaker, Peggy J. Farnham, Angela Tam, Vitor Onuchic, Robert A. Waterland, Misha Bilenky, James A. Thomson, Zhizhuo Zhang, Yaping Liu, Gerald Quon, Andrew J. Mungall, Steven J.M. Jones, Bradley E. Bernstein, Alexander Meissner, Melina Claussnitzer, Charles B. Epstein, Andreas R. Pfenning, Li-Huei Tsai, Laurie A. Boyer, Angela Yen, Ting Wang, Rajinder Kaul, Alireza Heravi-Moussavi, Danny Leung, Noam Shoresh, Michael T. McManus, Michael Stevens, John A. Stamatoyannopoulos, Mukul S. Bansal, Thea D. Tlsty, Susan J. Fisher, Manolis Kellis, Michael Q. Zhang, Aleksandar Milosavljevic, Viren Amin, Martin Hirst, Matthew D. Schultz, Joseph R. Ecker, Xinchen Wang, Jie Wu, Marco A. Marra, Kyle Siebenthall, Wei Wang, Ashwinikumar Kulkarni, Peter J. Sabo, R. Scott Hansen, Jianrong Wang, Michael J. Ziller, Richard A. Moore, Shane Neph, Richard C Sallari, Robert E. Thurman, Paz Polak, Wei Xie, Eric Chuah, Jason Ernst, Bing Ren, Nisha Rajagopal, Anshul Kundaje, Xin Zhou, Yi-Chieh Wu, Shamil R. Sunyaev, Ginell Elliott, Philippe Gascard, Soheil Feizi, Chibo Hong, R. Alan Harris, Ah Ram Kim, Philip L. De Jager, Rosa Karlic, R. David Hawkins, Matthew L. Eaton, Ryan Lister, Rebecca F. Lowdon, Annaick Carles, Elizabeta Gjoneska, David Haussler, Abhishek Sarkar, Nicholas A Sinnott-Armstrong, Wouter Meuleman, Lucas D. Ward, Kai How Farh, Richard Sandstrom, Arthur E. Beaudet, Theresa K. Canfield, Cristian Coarfa, Bo Zhang, Massachusetts Institute of Technology. Computer Science and Artificial Intelligence Laboratory, Massachusetts Institute of Technology. Department of Biology, Massachusetts Institute of Technology. Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology. Department of Electrical Engineering and Computer Science, Picower Institute for Learning and Memory, Kundaje, Anshul, Meuleman, Wouter, Ernst, Jason, Yen, Angela, Kheradpour, Pouya, Zhang, Zhizhuo, Wang, Jianrong, Ward, Lucas D., Sarkar, Abhishek Kulshreshtha, Quon, Gerald, Eaton, Matthew Lucas, Wu, Yi-Chieh, Pfenning, Andreas R., Wang, Xinchen, Claussnitzer, Melina, Liu, Yaping, Bansal, Mukul S., Feizi-Khankandi, Soheil, Kim, Ah Ram, Cowper Sal-lari, Richard, Sinnott-Armstrong, Nicholas A., Kellis, Manolis, Boyer, Laurie, Gjoneska, Elizabeta, and Tsai, Li-Huei

Subjects
Epigenomics, Datasets as Topic, ATAC-seq, Computational biology, Biology, Article, Epigenesis, Genetic, Histones, Reference Values, Computational epigenetics, Chromosomes, Human, Humans, Cell Lineage, Epigenetics, Cells, Cultured, Genetics, Regulation of gene expression, Multidisciplinary, Base Sequence, Genome, Human, Genetic Variation, DNA, Epigenome, DNA Methylation, Chromatin, Human genetics, Enhancer Elements, Genetic, Organ Specificity, RNA, Human genome, chromatin, histone, epigenome, tissue specificity, Genome-Wide Association Study
Abstract

The reference human genome sequence set the stage for studies of genetic variation and its association with human disease, but epigenomic studies lack a similar reference. To address this need, the NIH Roadmap Epigenomics Consortium generated the largest collection so far of human epigenomes for primary cells and tissues. Here we describe the integrative analysis of 111 reference human epigenomes generated as part of the programme, profiled for histone modification patterns, DNA accessibility, DNA methylation and RNA expression. We establish global maps of regulatory elements, define regulatory modules of coordinated activity, and their likely activators and repressors. We show that disease- and trait-associated genetic variants are enriched in tissue-specific epigenomic marks, revealing biologically relevant cell types for diverse human traits, and providing a resource for interpreting the molecular basis of human disease. Our results demonstrate the central role of epigenomic information for understanding gene regulation, cellular differentiation and human disease., National Human Genome Research Institute (U.S.) (RC1HG005334), National Human Genome Research Institute (U.S.) (R01HG004037), National Human Genome Research Institute (U.S.) (R01HG004037-S1), National Human Genome Research Institute (U.S.) (RO1NS078839), National Science Foundation (U.S.) (CAREER Award 1254200)

Published
2014

17. A comparative encyclopedia of DNA elements in the mouse genome

Author

Ting Wang, Matthew D. Rasmussen, Dana N. Levasseur, Thomas A. Reh, Fidencio Neri, Tanya Kutyavin, Peter J. Good, Katrina Learned, Kate R. Rosenbloom, Lei Hoon See, Cedric Notredame, Ross C. Hardison, Chris Zaleski, Gerd A. Blobel, Dmitri D. Pervouchine, Shane Neph, Ali Mortazavi, Tamer Kahveci, Arthur I. Skoultchi, Peter J. Sabo, Jorg Drenkow, Alex Reynolds, Rebecca F. Lowdon, Marella F. T. R. de Bruijn, John A. Stamatoyannopoulos, Yin Shen, Richard Humbert, Anthony Kirilusha, Sherman M. Weissman, Roderic Guigó, James Taylor, Paul Flicek, Kristen Lee, Shinny Vong, Xiaoyi Cao, Douglas Dunn, Alessandra Breschi, Elise A. Feingold, Michael A. Beer, Piper M. Treuting, Igor Antoshechkin, Thomas R. Gingeras, Georgi K. Marinov, Tyrone Ryba, Jin Lian, Christine M. Disteche, Javier Herrero, Eric Rynes, Sheng Zhong, Weisheng Wu, Richard Sandstrom, Gilberto DeSalvo, Michael Snyder, Meagan Fastuca, Miguel Pignatelli, Mark Groudine, Sarah Djebali, Nergiz Dogan, Rajinder Kaul, Giovanni Bussotti, Henry Amrhein, Daniel Bates, Matthew S. Wilken, Alexander Dobin, Manolis Kellis, Licia Selleri, Diane Trout, Morgan Diegel, David M. Gilbert, Zhihai Ma, Jeff Vierstra, Xiao Qiao Zhou, Theresa K. Canfield, Venkat S. Malladi, Zhen Ye, Anthony Shafer, Tejaswini Mishra, Yiing Lin, Samantha Kuan, Anshul Kundaje, Thalia Papayannopoulou, Pablo Prieto, Robert E. Thurman, Long Pham, Cricket A. Sloan, Olgert Denas, Kathryn Beal, Erika Giste, Andrea Tanzer, Katherine I. Fisher-Aylor, Shin Lin, M. A. Bender, Stuart H. Orkin, Carrie A. Davis, Benjamin D. Pope, Rachel Byron, Srikanta Gosh, Beatriz Lacerda de Sousa, R. Scott Hansen, Brian A. Williams, Yong Cheng, Kanwei Li, Dongwon Lee, Yanli Wang, Evan E. Eichler, Camden Jansen, Feng Yue, Deepti Jain, Miaohua Zhang, David McCleary, W. James Kent, Melissa S. Cline, Kai Hsin Chang, Leslie B. Adams, Robert S. Harris, Ghia Euskirchen, Christapher S. Morrissey, Alexander Y. Rudensky, Philip Cayting, Drew T. Erickson, Eric Haugen, Michael J. Pazin, Vanessa M. Kirkup, Yi-Chieh Wu, Trupti Kawli, Mukul S. Bansal, Cheryl A. Keller, Lee Edsall, Robert M. Samstein, Bing Ren, Miguel Santos, Steven Z. Josefowicz, Barbara J. Wold, Julien Lagarde, Alan P. Boyle, Mitchell J. Weiss, Audra K. Johnson, Massachusetts Institute of Technology. Computer Science and Artificial Intelligence Laboratory, Massachusetts Institute of Technology. Department of Electrical Engineering and Computer Science, Wu, Yi-Chieh, Rasmussen, Matthew D., Bansal, Mukul S., and Kellis, Manolis

Subjects
Epigenomics, DNA Replication, Biology, Regulatory Sequences, Nucleic Acid, ENCODE, Genome, Article, Mice, Species Specificity, Animals, Deoxyribonuclease I, Humans, Cell Lineage, Gene Regulatory Networks, Scaffold/matrix attachment region, Gene, ChIA-PET, Conserved Sequence, Genetics, Multidisciplinary, Mouse genome, Molecular Sequence Annotation, Genomics, Chromatin, Gene Expression Regulation, RNA, Human genome, Transcriptome, Genome-Wide Association Study, Transcription Factors
Abstract

The laboratory mouse shares the majority of its protein-coding genes with humans, making it the premier model organism in biomedical research, yet the two mammals differ in significant ways. To gain greater insights into both shared and species-specific transcriptional and cellular regulatory programs in the mouse, the Mouse ENCODE Consortium has mapped transcription, DNase I hypersensitivity, transcription factor binding, chromatin modifications and replication domains throughout the mouse genome in diverse cell and tissue types. By comparing with the human genome, we not only confirm substantial conservation in the newly annotated potential functional sequences, but also find a large degree of divergence of sequences involved in transcriptional regulation, chromatin state and higher order chromatin organization. Our results illuminate the wide range of evolutionary forces acting on genes and their regulatory regions, and provide a general resource for research into mammalian biology and mechanisms of human diseases. This work is funded by grants R01HG003991 (B.R.), 1U54HG007004 (T.R.G.), 3RC2HG005602 (M.P.S.), GM083337 and GM085354 (D.M.G.), F31CA165863 (B.D.P.), RC2HG005573 and R01DK065806 (R.C.H.) from the National Institutes of Health, and BIO2011-26205 from the Spanish Plan Nacional and ERC 294653 (to R.G.). J.V. is supported by a National Science Foundation Graduate Research Fellowship under grant no. DGE-071824. K.B., M.P., J.H. and P.F. acknowledge the Wellcome Trust (grant number 095908), the NHGRI (grant number U01HG004695) and the European Molecular Biology Laboratory. We thank G. Hon for helping the analysis of high-throughput enhancer validation. L.S. is supported by R01HD043997-09. S.L. was supported by grants F32HL110473 and K99HL119617.

Published
2014

18. Exploring long-range genome interactions using the WashU Epigenome Browser

Author

Ting Wang, Heather A. Lawson, Rebecca F. Lowdon, Xin Zhou, Daofeng Li, Pamela A. F. Madden, and Joseph F. Costello

Subjects
Genome, Range (biology), Genome informatics, Programming Languages, Cell Biology, Computational biology, Epigenome, Biology, Molecular Biology, Biochemistry, Article, Biotechnology
Published
2013

19. An encyclopedia of mouse DNA elements (Mouse ENCODE)

Author

David M. Gilbert, A Sandra Stehling, Zhihai Ma, Barbara J. Wold, Sonali Jha, Theresa K. Canfield, Julien Lagarde, Vanessa M. Kirkup, W. James Kent, Olgert Denas, M. A. Bender, Erica Giste, Mark Groudine, Yong Cheng, Sarah Djebali, Tyrone Ryba, Marta Byrska-Bishop, Jin Lian, Zhen Ye, Philip Cayting, Michael Snyder, Cheryl A. Keller, Alexander Dobin, Anthony Kiralusha, Tejaswini Mishra, Gayathri Balasundaram, Wulan Deng, Gaurav Jain, Ross C. Hardison, Michael J. Pazin, Stephen G. Landt, Takayo Sasaki, Mia Zhang, Manoj Hariharan, Job Dekker, Peter J. Sabo, Diane Trout, Bing Ren, Mitchell J. Weiss, Audra K. Johnson, Sherman M. Weissman, Deepti Jain, Venkat S. Malladi, Huaien Wang, David McCleary, Melissa S. Cline, Robert E. Thurman, Weisheng Wu, Samantha Kuan, Gregory E. Crawford, Yin Shen, Daniel Blankenberg, Wei Lin, Thomas R. Gingeras, Vaughan Roach, Roderic Guigó, James Taylor, Rajinder Kaul, Gilberto DeSalvo, Henry Amrhein, Carrie A. Davis, Lee Edsall, Amartya Sanyal, Katherine I. Fisher-Aylor, Feng Yue, Ali Mortazavi, Brian A. Williams, Gerd A. Blobel, Rebecca F. Lowdon, Chris Zaleski, Bryan R. Lajoie, John A. Stamatoyannopoulos, Peter J. Good, Katrina Learned, Christopher T. Morrissey, Georgi K. Marinov, Kaun-Bei Chen, Richard Sandstrom, Meagan Fastuca, Elise A. Feingold, Kate R. Rosenbloom, Max Pimkin, Leslie B Adams, Chenghai Xue, Rachel Byron, and Swathi Ashok Kumar

Subjects
ENCODE Project, Ratolins (Animals de laboratori), InformationSystems_INFORMATIONINTERFACESANDPRESENTATION(e.g.,HCI), Genomics, RNA-Seq, mouse genome, Data_CODINGANDINFORMATIONTHEORY, comparative genomics, Biology, ENCODE, Genome, chemistry.chemical_compound, Mice, DNaseI hypersensitive sites, Animals, Humans, Comparative genomics, Genetics, Internet, Genome, Human, histone modifications, Molecular Sequence Annotation, Human genetics, DNA binding site, ChIP-seq, Genòmica, ComputingMethodologies_PATTERNRECOGNITION, chemistry, transcription factor binding sites, Open Letter, RNA-seq, Databases, Nucleic Acid, transcriptome, DNA
Abstract

To complement the human Encyclopedia of DNA Elements (ENCODE) project and to enable a broad range of mouse genomics efforts, the Mouse ENCODE Consortium is applying the same experimental pipelines developed for human ENCODE to annotate the mouse genome.

Published
2012

20. A User's Guide to the Encyclopedia of DNA Elements (ENCODE)

Author

Zhi Lu, Giltae Song, Troy W. Whitfield, Vishwanath R. Iyer, Teresa Vales, Angelika Merkel, Max Libbrecht, David Haussler, Ting Wang, Kristen Lee, Lingyun Song, Richard M. Myers, Alfonso Valencia, Rachel A. Harte, Xiaoqin Xu, Lucas D. Ward, Hazuki Takahashi, Nathan C. Sheffield, Thomas Derrien, Georgi K. Marinov, Eric D. Nguyen, Bernard B. Suh, Brian J. Raney, Richard Sandstrom, Thomas D. Tullius, Benoit Miotto, Alexander Dobin, Youhan Xu, Lukas Habegger, Ian Dunham, Brian A. Risk, Paul G. Giresi, Morgan C. Giddings, Hualin Xi, Anshul Kundaje, Robert S. Harris, Devin Absher, Peter J. Bickel, Yanbao Yu, Browen Aken, Colin Kingswood, Bryan R. Lajoie, Peter J. Good, Katrina Learned, Laura Elnitski, Shirley Pepke, Brandon King, Piero Carninci, Xinqiong Yang, Ghia Euskirchen, Kathryn Beal, Christelle Borel, Michael Muratet, Robert L. Grossman, David G. Knowles, Zarmik Moqtaderi, Veronika Boychenko, Steven P. Wilder, Michael L. Tress, Florencia Pauli, Alan P. Boyle, Andrea Tanzer, Philipp Kapranov, Serafim Batzoglou, Audra K. Johnson, Jun Neri, Nitin Bhardwaj, Elise A. Feingold, Venkat S. Malladi, Michael M. Hoffman, William Stafford Noble, Andrea Sboner, Mark Gerstein, Stephanie L. Parker, Jacqueline Dumais, Felix Schlesinger, Deborah R. Winter, Randall H. Brown, Thanh Truong, Rebecca F. Lowdon, Paolo Ribeca, Brooke Rhead, Peggy J. Farnham, Krista Thibeault, Terrence S. Furey, Donna Karolchik, Alec Victorsen, Xiaoan Ruan, Rehab F. Abdelhamid, Amy S. Nesmith, Jing Wang, Nicholas M. Luscombe, Alina R. Cao, Diane Trout, Teri Slifer, Peter E. Newburger, Cricket A. Sloan, Dimitra Lotakis, Stephen M. J. Searle, Ali Mortazavi, Alexandra Bignell, Alex Reynolds, Orion J. Buske, Chris Zaleski, Theresa K. Canfield, Ian Bell, Jin Lian, Vanessa K. Swing, Katalin Toth Fejes, Catherine Ucla, Robert E. Thurman, Jacqueline Chrast, Wei Lin, Tim Hubbard, Gary Saunders, Minyi Shi, Vihra Sotirova, Sherman M. Weissman, Jason D. Lieb, Richard Humbert, Kevin M. Bowling, Assaf Gordon, Tarjei S. Mikkelsen, Jing Leng, Thomas R. Gingeras, Fabian Grubert, Nader Jameel, Jost Vielmetter, Hannah Monahan, Preti Jain, Lindsay L. Waite, Tony Shafer, Joel Rozowsky, Michael Coyne, Brian Reed, M. Kay, Harsha P. Gunawardena, Ross C. Hardison, Gavin Sherlock, Alexandra Charos, Joseph D. Fleming, Ann S. Zweig, Jason Gertz, Rajinder Kaul, Xianjun Dong, Alexandre Reymond, Carrie A. Davis, Haiyan Huang, Chao Cheng, Marco Mariotti, Phil Lacroute, Jason A. Dilocker, Kenneth McCue, R. Robilotto, Stylianos E. Antonarakis, Sridar V. Chittur, Justin Jee, Barbara J. Wold, Sudipto K. Chakrabortty, Erica Dumais, Amartya Sanyal, Nathan Boley, Tianyuan Wang, Julien Lagarde, Anthony Kirilusha, Jonathan B. Preall, Kevin Roberts, Erika Giste, Hugo Y. K. Lam, Alvis Brazma, Gregory J. Hannon, Eric Rynes, Philippe Batut, Kevin Struhl, Margus Lukk, Manching Ku, Suganthi Balasubramanian, Sonali Jha, Jorg Drenkow, W. James Kent, Michael Snyder, Jie Wang, Anna Battenhouse, Charles B. Epstein, Rami Rauch, Christopher Shestak, John A. Stamatoyannopoulos, Gaurab Mukherjee, Cédric Howald, Tanya Kutyavin, Huaien Wang, Scott A. Tenenbaum, Wan Ting Poh, Kate R. Rosenbloom, Manolis Kellis, Pauline A. Fujita, Linfeng Wu, Anita Bansal, Molly Weaver, Linda L. Grasfeder, Peter J. Sabo, Qiang Li, Melissa S. Cline, Robert M. Kuhn, Darin London, Seth Frietze, Atif Shahab, Shane Neph, Damian Keefe, James B. Brown, Mark Diekhans, Webb Miller, Katherine Aylor Fisher, Jiang Du, Hadar H. Sheffer, Sarah Djebali, Frank Doyle, Nathan Lamarre-Vincent, Chia-Lin Wei, Laura A.L. Dillon, Jennifer Harrow, Robert C. Altshuler, Tyler Alioto, Raymond K. Auerbach, Adam Frankish, Rebekka O. Sprouse, Patrick J. Collins, E. Christopher Partridge, Zheng Liu, Yoichiro Shibata, Elliott H. Margulies, Abigail K. Ebersol, Kimberly A. Showers, Eric D. Green, Krishna M. Roskin, Job Dekker, Barbara N. Pusey, Ekta Khurana, Gilberto DeSalvo, Yijun Ruan, Hao Wang, Jainab Khatun, Henriette O'Geen, Alexej Abyzov, Brian Williams, Ryan M. McDaniell, Maya Kasowski, Manoj Hariharan, Felix Kokocinski, Gloria Despacio-Reyes, Zhancheng Zhang, Subhradip Karmakar, Ewan Birney, Koon-Kiu Yan, Xian Chen, Shinny Vong, Daniel Sobral, Nick Bild, Seul K.C. Kim, Timo Lassmann, Li Wang, Minerva E. Sanchez, Vaughan Roach, Theodore Gibson, Stephen C. J. Parker, Michael F. Lin, Patrick A. Navas, Laurence R. Meyer, Luiz O. F. Penalva, Bradley E. Bernstein, Kevin P. White, Emilie Aït Yahya Graison, Juan M. Vaquerizas, Sushma Iyengar, Kimberly M. Newberry, Akshay Bhinge, Xiaolan Zhang, Kim Bell, Yoshihide Hayashizaki, Lucas Lochovsky, Noam Shoresh, Hagen Tilgner, Philip Cayting, Dorrelyn Patacsil, Timothy E. Reddy, Eric Haugen, Katherine E. Varley, M. van Baren, Nathan D. Trinklein, Bum Kyu Lee, Tristan Frum, Marianne Lindahl-Allen, Timothy Durham, Roderic Guigó, Christopher W. Maier, Micha Sammeth, Debasish Raha, Timothy R. Dreszer, Benedict Paten, Robbyn Issner, Michael R. Brent, Kevin Y. Yip, Kim Blahnik, Jason Ernst, Zhiping Weng, Henry Amrhein, Arend Sidow, Javier Herrero, Hui Gao, Stephen G. Landt, Pouya Kheradpour, Galt P. Barber, Gregory E. Crawford, Toby Hunt, HudsonAlpha Institute for Biotechnology [Huntsville, AL], ENCODE Project Consortium : Myers RM, Stamatoyannopoulos J, Snyder M, Dunham I, Hardison RC, Bernstein BE, Gingeras TR, Kent WJ, Birney E, Wold B, Crawford GE, Bernstein BE, Epstein CB, Shoresh N, Ernst J, Mikkelsen TS, Kheradpour P, Zhang X, Wang L, Issner R, Coyne MJ, Durham T, Ku M, Truong T, Ward LD, Altshuler RC, Lin MF, Kellis M, Gingeras TR, Davis CA, Kapranov P, Dobin A, Zaleski C, Schlesinger F, Batut P, Chakrabortty S, Jha S, Lin W, Drenkow J, Wang H, Bell K, Gao H, Bell I, Dumais E, Dumais J, Antonarakis SE, Ucla C, Borel C, Guigo R, Djebali S, Lagarde J, Kingswood C, Ribeca P, Sammeth M, Alioto T, Merkel A, Tilgner H, Carninci P, Hayashizaki Y, Lassmann T, Takahashi H, Abdelhamid RF, Hannon G, Fejes-Toth K, Preall J, Gordon A, Sotirova V, Reymond A, Howald C, Graison E, Chrast J, Ruan Y, Ruan X, Shahab A, Ting Poh W, Wei CL, Crawford GE, Furey TS, Boyle AP, Sheffield NC, Song L, Shibata Y, Vales T, Winter D, Zhang Z, London D, Wang T, Birney E, Keefe D, Iyer VR, Lee BK, McDaniell RM, Liu Z, Battenhouse A, Bhinge AA, Lieb JD, Grasfeder LL, Showers KA, Giresi PG, Kim SK, Shestak C, Myers RM, Pauli F, Reddy TE, Gertz J, Partridge EC, Jain P, Sprouse RO, Bansal A, Pusey B, Muratet MA, Varley KE, Bowling KM, Newberry KM, Nesmith AS, Dilocker JA, Parker SL, Waite LL, Thibeault K, Roberts K, Absher DM, Wold B, Mortazavi A, Williams B, Marinov G, Trout D, Pepke S, King B, McCue K, Kirilusha A, DeSalvo G, Fisher-Aylor K, Amrhein H, Vielmetter J, Sherlock G, Sidow A, Batzoglou S, Rauch R, Kundaje A, Libbrecht M, Margulies EH, Parker SC, Elnitski L, Green ED, Hubbard T, Harrow J, Searle S, Kokocinski F, Aken B, Frankish A, Hunt T, Despacio-Reyes G, Kay M, Mukherjee G, Bignell A, Saunders G, Boychenko V, Van Baren M, Brown RH, Khurana E, Balasubramanian S, Zhang Z, Lam H, Cayting P, Robilotto R, Lu Z, Guigo R, Derrien T, Tanzer A, Knowles DG, Mariotti M, James Kent W, Haussler D, Harte R, Diekhans M, Kellis M, Lin M, Kheradpour P, Ernst J, Reymond A, Howald C, Graison EA, Chrast J, Tress M, Rodriguez JM, Snyder M, Landt SG, Raha D, Shi M, Euskirchen G, Grubert F, Kasowski M, Lian J, Cayting P, Lacroute P, Xu Y, Monahan H, Patacsil D, Slifer T, Yang X, Charos A, Reed B, Wu L, Auerbach RK, Habegger L, Hariharan M, Rozowsky J, Abyzov A, Weissman SM, Gerstein M, Struhl K, Lamarre-Vincent N, Lindahl-Allen M, Miotto B, Moqtaderi Z, Fleming JD, Newburger P, Farnham PJ, Frietze S, O'Geen H, Xu X, Blahnik KR, Cao AR, Iyengar S, Stamatoyannopoulos JA, Kaul R, Thurman RE, Wang H, Navas PA, Sandstrom R, Sabo PJ, Weaver M, Canfield T, Lee K, Neph S, Roach V, Reynolds A, Johnson A, Rynes E, Giste E, Vong S, Neri J, Frum T, Johnson EM, Nguyen ED, Ebersol AK, Sanchez ME, Sheffer HH, Lotakis D, Haugen E, Humbert R, Kutyavin T, Shafer T, Dekker J, Lajoie BR, Sanyal A, James Kent W, Rosenbloom KR, Dreszer TR, Raney BJ, Barber GP, Meyer LR, Sloan CA, Malladi VS, Cline MS, Learned K, Swing VK, Zweig AS, Rhead B, Fujita PA, Roskin K, Karolchik D, Kuhn RM, Haussler D, Birney E, Dunham I, Wilder SP, Keefe D, Sobral D, Herrero J, Beal K, Lukk M, Brazma A, Vaquerizas JM, Luscombe NM, Bickel PJ, Boley N, Brown JB, Li Q, Huang H, Gerstein M, Habegger L, Sboner A, Rozowsky J, Auerbach RK, Yip KY, Cheng C, Yan KK, Bhardwaj N, Wang J, Lochovsky L, Jee J, Gibson T, Leng J, Du J, Hardison RC, Harris RS, Song G, Miller W, Haussler D, Roskin K, Suh B, Wang T, Paten B, Noble WS, Hoffman MM, Buske OJ, Weng Z, Dong X, Wang J, Xi H, Tenenbaum SA, Doyle F, Penalva LO, Chittur S, Tullius TD, Parker SC, White KP, Karmakar S, Victorsen A, Jameel N, Bild N, Grossman RL, Snyder M, Landt SG, Yang X, Patacsil D, Slifer T, Dekker J, Lajoie BR, Sanyal A, Weng Z, Whitfield TW, Wang J, Collins PJ, Trinklein ND, Partridge EC, Myers RM, Giddings MC, Chen X, Khatun J, Maier C, Yu Y, Gunawardena H, Risk B, Feingold EA, Lowdon RF, Dillon LA, Good PJ, Harrow J, Searle S., Becker, Peter B, Broad Institute of MIT and Harvard, Lincoln Laboratory, Massachusetts Institute of Technology. Computer Science and Artificial Intelligence Laboratory, Massachusetts Institute of Technology. Department of Electrical Engineering and Computer Science, Massachusetts Institute of Technology. Department of Physics, Kellis, Manolis, Epstein, Charles B., Bernstein, Bradley E., Shoresh, Noam, Ernst, Jason, Mikkelsen, Tarjei Sigurd, Kheradpour, Pouya, Zhang, Xiaolan, Wang, Li, Issner, Robbyn, Coyne, Michael J., Durham, Timothy, Ku, Manching, Truong, Thanh, Ward, Lucas D., Altshuler, Robert Charles, Lin, Michael F., ENCODE Project Consortium, Antonarakis, Stylianos, and Miotto, Benoit

Subjects
RNA, Messenger/genetics, [SDV]Life Sciences [q-bio], Messenger, Genoma humà, Genome, Medical and Health Sciences, 0302 clinical medicine, Models, ddc:576.5, Biology (General), Conserved Sequence, Genetics, 0303 health sciences, General Neuroscience, RNA-Binding Proteins, Genomics, Biological Sciences, Chromatin, 3. Good health, [SDV] Life Sciences [q-bio], DNA-Binding Proteins, Gene Components, 030220 oncology & carcinogenesis, DNA methylation, Encyclopedia, HIV/AIDS, Proteïnes de la sang -- Aspectes genètics, General Agricultural and Biological Sciences, Databases, Nucleic Acid, Human, Research Article, Quality Control, Process (engineering), QH301-705.5, 1.1 Normal biological development and functioning, Computational biology, Biology, ENCODE, General Biochemistry, Genetics and Molecular Biology, Chromatin/metabolism, Vaccine Related, 03 medical and health sciences, Databases, Genetic, Underpinning research, Humans, RNA, Messenger, RNA-Binding Proteins/genetics/metabolism, Vaccine Related (AIDS), Gene, 030304 developmental biology, Internet, General Immunology and Microbiology, Nucleic Acid, Agricultural and Veterinary Sciences, Base Sequence, Models, Genetic, Genome, Human, Prevention, Human Genome, Computational Biology, DNA Methylation, ENCODE Project Consortium, Gene Expression Regulation, DNA-Binding Proteins/genetics/metabolism, RNA, Human genome, Immunization, Generic health relevance, Developmental Biology
Abstract

The mission of the Encyclopedia of DNA Elements (ENCODE) Project is to enable the scientific and medical communities to interpret the human genome sequence and apply it to understand human biology and improve health. The ENCODE Consortium is integrating multiple technologies and approaches in a collective effort to discover and define the functional elements encoded in the human genome, including genes, transcripts, and transcriptional regulatory regions, together with their attendant chromatin states and DNA methylation patterns. In the process, standards to ensure high-quality data have been implemented, and novel algorithms have been developed to facilitate analysis. Data and derived results are made available through a freely accessible database. Here we provide an overview of the project and the resources it is generating and illustrate the application of ENCODE data to interpret the human genome., National Human Genome Research Institute (U.S.), National Institutes of Health (U.S.)

Published
2011

22. Tissue-specific DNA methylation is conserved across human, mouse, and rat, and driven by primary sequence conservation

Author

Jia Zhou, Renee L. Sears, Xiaoyun Xing, Bo Zhang, Daofeng Li, Nicole B. Rockweiler, Hyo Sik Jang, Mayank N.K. Choudhary, Hyung Joo Lee, Rebecca F. Lowdon, Jason Arand, Brianne Tabers, C. Charles Gu, Theodore J. Cicero, and Ting Wang

Subjects
DNA methylation, Epigenetic conservation, Tissue-specific, Comparative genomics, Comparative epigenomics, Biotechnology, TP248.13-248.65, Genetics, QH426-470
Abstract

Abstract Background Uncovering mechanisms of epigenome evolution is an essential step towards understanding the evolution of different cellular phenotypes. While studies have confirmed DNA methylation as a conserved epigenetic mechanism in mammalian development, little is known about the conservation of tissue-specific genome-wide DNA methylation patterns. Results Using a comparative epigenomics approach, we identified and compared the tissue-specific DNA methylation patterns of rat against those of mouse and human across three shared tissue types. We confirmed that tissue-specific differentially methylated regions are strongly associated with tissue-specific regulatory elements. Comparisons between species revealed that at a minimum 11-37% of tissue-specific DNA methylation patterns are conserved, a phenomenon that we define as epigenetic conservation. Conserved DNA methylation is accompanied by conservation of other epigenetic marks including histone modifications. Although a significant amount of locus-specific methylation is epigenetically conserved, the majority of tissue-specific DNA methylation is not conserved across the species and tissue types that we investigated. Examination of the genetic underpinning of epigenetic conservation suggests that primary sequence conservation is a driving force behind epigenetic conservation. In contrast, evolutionary dynamics of tissue-specific DNA methylation are best explained by the maintenance or turnover of binding sites for important transcription factors. Conclusions Our study extends the limited literature of comparative epigenomics and suggests a new paradigm for epigenetic conservation without genetic conservation through analysis of transcription factor binding sites.

Published
2017
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