Integrative analysis of 111 reference human epigenomes
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 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 Moore, Eric Chuah, Angela Tam, Theresa K Canfield, R Scott Hansen, Rajinder Kaul, Peter J Sabo, Mukul S Bansal, Annaick Carles, Jesse R Dixon, Kai-How Farh, Soheil Feizi, Rosa Karlic, Ah-Ram Kim, Ashwinikumar Kulkarni, Daofeng Li, Rebecca 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, 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 Sunyaev, James A Thomson, Thea D Tlsty, Li-Huei Tsai, Wei Wang, 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, Manolis Kellis, 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 Quon, Richard S Sandstrom, Matthew L Eaton, Yi-Chieh Wu, Andreas 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 Moore, Eric Chuah, Angela Tam, Theresa K Canfield, R Scott Hansen, Rajinder Kaul, Peter J Sabo, Mukul S Bansal, Annaick Carles, Jesse R Dixon, Kai-How Farh, Soheil Feizi, Rosa Karlic, Ah-Ram Kim, Ashwinikumar Kulkarni, Daofeng Li, Rebecca 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, Xin Zhou, Nezar Abdennur, Mazhar Adli, Martin Akerman, Luis Barrera, Jessica Antosiewicz-Bourget, Tracy Ballinger, Michael J Barnes, Daniel Bates, Robert J A Bell, David A Bennett, Katherine Bianco, Christoph Bock, Patrick Boyle, Jan Brinchmann, Pedro Caballero-Campo, Raymond Camahort, Marlene J Carrasco-Alfonso, Timothy Charnecki, Huaming Chen, Zhao Chen, Jeffrey B Cheng, Stephanie Cho, Andy Chu, Wen-Yu Chung, Chad Cowan, Qixia Athena Deng, Vikram Deshpande, Morgan Diegel, Bo Ding, Timothy Durham, Lorigail Echipare, Lee Edsall, David Flowers, Olga Genbacev-Krtolica, Casey Gifford, Shawn Gillespie, Erika Giste, Ian A Glass, Andreas Gnirke, Matthew Gormley, Hongcang Gu, Junchen Gu, David A Hafler, Matthew J Hangauer, Manoj Hariharan, Meital Hatan, Eric Haugen, Yupeng He, Shelly Heimfeld, Sarah Herlofsen, Zhonggang Hou, Richard Humbert, Robbyn Issner, Andrew R Jackson, Haiyang Jia, Peng Jiang, Audra K Johnson, Theresa Kadlecek, Baljit Kamoh, Mirhan Kapidzic, Jim Kent, Audrey Kim, Markus Kleinewietfeld, Sarit Klugman, Jayanth Krishnan, Samantha Kuan, Tanya Kutyavin, Ah-Young Lee, Kristen Lee, Jian Li, Nan Li, Yan Li, Keith L Ligon, Shin Lin, Yiing Lin, Jie Liu, Yuxuan Liu, C John Luckey, Yussanne P Ma, Cecile Maire, Alexander Marson, John S Mattick, Michael Mayo, Michael McMaster, Hayden Metsky, Tarjei Mikkelsen, Diane Miller, Mohammad Miri, Eran Mukamel, Raman P Nagarajan, Fidencio Neri, Joseph Nery, Tung Nguyen, Henriette O'Geen, Sameer Paithankar, Thalia Papayannopoulou, Mattia Pelizzola, Patrick Plettner, Nicholas E Propson, Sriram Raghuraman, Brian J Raney, Anthony Raubitschek, Alex P Reynolds, Hunter Richards, Kevin Riehle, Paolo Rinaudo, Joshua F Robinson, Nicole B Rockweiler, Evan Rosen, Eric Rynes, Jacqueline Schein, Renee Sears, Terrence Sejnowski, Anthony Shafer, Li Shen, Robert Shoemaker, Mahvash Sigaroudinia, Igor Slukvin, Sandra Stehling-Sun, Ron Stewart, Sai Lakshmi Subramanian, Kran Suknuntha, Scott Swanson, Shulan Tian, Hannah Tilden, Linus Tsai, Mark Urich, Ian Vaughn, Jeff Vierstra, Shinny Vong, Ulrich Wagner, Hao Wang, Tao Wang, Yunfei Wang, Arthur Weiss, Holly Whitton, Andre Wildberg, Heather Witt, Kyoung-Jae Won, Mingchao Xie, Xiaoyun Xing, Iris Xu, Zhenyu Xuan, Zhen Ye, Chia-an Yen, Pengzhi Yu, Xian Zhang, Xiaolan Zhang, Jianxin Zhao, Yan Zhou, Jiang Zhu, Yun Zhu, Steven Ziegler, 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 Sunyaev, James A Thomson, Thea D Tlsty, Li-Huei Tsai, Wei Wang, 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, Manolis Kellis, Bradley E Bernstein, Joseph F Costello, Joseph R Ecker, Martin Hirst, Alexander Meissner, Aleksandar Milosavljevic, Bing Ren, John A Stamatoyannopoulos, Ting Wang, Manolis Kellis, 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 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 Moore, Eric Chuah, Angela Tam, Theresa K Canfield, R Scott Hansen, Rajinder Kaul, Peter J Sabo, Mukul S Bansal, Annaick Carles, Jesse R Dixon, Kai-How Farh, Soheil Feizi, Rosa Karlic, Ah-Ram Kim, Ashwinikumar Kulkarni, Daofeng Li, Rebecca 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, 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 Sunyaev, James A Thomson, Thea D Tlsty, Li-Huei Tsai, Wei Wang, 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, Manolis Kellis, 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 Quon, Richard S Sandstrom, Matthew L Eaton, Yi-Chieh Wu, Andreas 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 Moore, Eric Chuah, Angela Tam, Theresa K Canfield, R Scott Hansen, Rajinder Kaul, Peter J Sabo, Mukul S Bansal, Annaick Carles, Jesse R Dixon, Kai-How Farh, Soheil Feizi, Rosa Karlic, Ah-Ram Kim, Ashwinikumar Kulkarni, Daofeng Li, Rebecca 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, Xin Zhou, Nezar Abdennur, Mazhar Adli, Martin Akerman, Luis Barrera, Jessica Antosiewicz-Bourget, Tracy Ballinger, Michael J Barnes, Daniel Bates, Robert J A Bell, David A Bennett, Katherine Bianco, Christoph Bock, Patrick Boyle, Jan Brinchmann, Pedro Caballero-Campo, Raymond Camahort, Marlene J Carrasco-Alfonso, Timothy Charnecki, Huaming Chen, Zhao Chen, Jeffrey B Cheng, Stephanie Cho, Andy Chu, Wen-Yu Chung, Chad Cowan, Qixia Athena Deng, Vikram Deshpande, Morgan Diegel, Bo Ding, Timothy Durham, Lorigail Echipare, Lee Edsall, David Flowers, Olga Genbacev-Krtolica, Casey Gifford, Shawn Gillespie, Erika Giste, Ian A Glass, Andreas Gnirke, Matthew Gormley, Hongcang Gu, Junchen Gu, David A Hafler, Matthew J Hangauer, Manoj Hariharan, Meital Hatan, Eric Haugen, Yupeng He, Shelly Heimfeld, Sarah Herlofsen, Zhonggang Hou, Richard Humbert, Robbyn Issner, Andrew R Jackson, Haiyang Jia, Peng Jiang, Audra K Johnson, Theresa Kadlecek, Baljit Kamoh, Mirhan Kapidzic, Jim Kent, Audrey Kim, Markus Kleinewietfeld, Sarit Klugman, Jayanth Krishnan, Samantha Kuan, Tanya Kutyavin, Ah-Young Lee, Kristen Lee, Jian Li, Nan Li, Yan Li, Keith L Ligon, Shin Lin, Yiing Lin, Jie Liu, Yuxuan Liu, C John Luckey, Yussanne P Ma, Cecile Maire, Alexander Marson, John S Mattick, Michael Mayo, Michael McMaster, Hayden Metsky, Tarjei Mikkelsen, Diane Miller, Mohammad Miri, Eran Mukamel, Raman P Nagarajan, Fidencio Neri, Joseph Nery, Tung Nguyen, Henriette O'Geen, Sameer Paithankar, Thalia Papayannopoulou, Mattia Pelizzola, Patrick Plettner, Nicholas E Propson, Sriram Raghuraman, Brian J Raney, Anthony Raubitschek, Alex P Reynolds, Hunter Richards, Kevin Riehle, Paolo Rinaudo, Joshua F Robinson, Nicole B Rockweiler, Evan Rosen, Eric Rynes, Jacqueline Schein, Renee Sears, Terrence Sejnowski, Anthony Shafer, Li Shen, Robert Shoemaker, Mahvash Sigaroudinia, Igor Slukvin, Sandra Stehling-Sun, Ron Stewart, Sai Lakshmi Subramanian, Kran Suknuntha, Scott Swanson, Shulan Tian, Hannah Tilden, Linus Tsai, Mark Urich, Ian Vaughn, Jeff Vierstra, Shinny Vong, Ulrich Wagner, Hao Wang, Tao Wang, Yunfei Wang, Arthur Weiss, Holly Whitton, Andre Wildberg, Heather Witt, Kyoung-Jae Won, Mingchao Xie, Xiaoyun Xing, Iris Xu, Zhenyu Xuan, Zhen Ye, Chia-an Yen, Pengzhi Yu, Xian Zhang, Xiaolan Zhang, Jianxin Zhao, Yan Zhou, Jiang Zhu, Yun Zhu, Steven Ziegler, 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 Sunyaev, James A Thomson, Thea D Tlsty, Li-Huei Tsai, Wei Wang, 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, Manolis Kellis, Bradley E Bernstein, Joseph F Costello, Joseph R Ecker, Martin Hirst, Alexander Meissner, Aleksandar Milosavljevic, Bing Ren, John A Stamatoyannopoulos, Ting Wang, Manolis Kellis
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.
Figures
References
- Rivera CM, Ren B. Mapping human epigenomes. Cell. 2013;155:39–55.
- Zhou VW, Goren A, Bernstein BE. Charting histone modifications and the functional organization of mammalian genomes. Nat Rev Genet. 2011;12:7–18.
- Jones PA. Functions of DNA methylation: islands, start sites, gene bodies and beyond. Nat Rev Genet. 2012;13:484–492.
- Smith ZD, Meissner A. DNA methylation: roles in mammalian development. Nat Rev Genet. 2013;14:204–220.
- Wang Z, Gerstein M, Snyder M. RNA-Seq: a revolutionary tool for transcriptomics. Nat Rev Genet. 2009;10:57–63.
- Park PJ. ChIP-seq: advantages and challenges of a maturing technology. Nat Rev Genet. 2009;10:669–680.
- Thurman RE, et al. The accessible chromatin landscape of the human genome. Nature. 2012;489:75–82.
- Mortazavi A, Williams BA, McCue K, Schaeffer L, Wold B. Mapping and quantifying mammalian transcriptomes by RNA-Seq. Nat Methods. 2008;5:621–628.
- Ernst J, et al. Mapping and analysis of chromatin state dynamics in nine human cell types. Nature. 2011;473:43–49.
- Heintzman ND, et al. Distinct and predictive chromatin signatures of transcriptional promoters and enhancers in the human genome. Nat Genet. 2007;39:311–318.
- Xie W, et al. Epigenomic analysis of multilineage differentiation of human embryonic stem cells. Cell. 2013;153:1134–1148.
- Zhu J, et al. Genome-wide chromatin state transitions associated with developmental and environmental cues. Cell. 2013;152:642–654.
- Neph S, et al. An expansive human regulatory lexicon encoded in transcription factor footprints. Nature. 2012;489:83–90.
- Maurano MT, et al. Systematic localization of common disease-associated variation in regulatory DNA. Science. 2012;337:1190–1195.
- Bernstein BE, et al. The NIH Roadmap Epigenomics Mapping Consortium. Nat Biotechnol. 2010;28:1045–1048.
- Mikkelsen TS, et al. Genome-wide maps of chromatin state in pluripotent and lineage- committed cells. Nature. 2007;448:553–560.
- Barski A, et al. High-resolution profiling of histone methylations in the human genome. Cell. 2007;129:823–837.
- John S, et al. Genome-scale mapping of DNase I hypersensitivity. Curr Protoc Mol Biol. 2013 Chapter 27, Unit 21 27.
- Lister R, et al. Human DNA methylomes at base resolution show widespread epigenomic differences. Nature. 2009;462:315–322.
- Meissner A, et al. Reduced representation bisulfite sequencing for comparative high-resolution DNA methylation analysis. Nucleic Acids Res. 2005;33:5868–5877.
- Weber M, et al. Chromosome-wide and promoter-specific analyses identify sites of differential DNA methylation in normal and transformed human cells. Nat Genet. 2005;37:853–862.
- Maunakea AK, et al. Conserved role of intragenic DNA methylation in regulating alternative promoters. Nature. 2010;466:253–257.
- ENCODE_Project_Consortium An integrated encyclopedia of DNA elements in the human genome. Nature. 2012;489:57–74.
- Bernstein BE, et al. Genomic maps and comparative analysis of histone modifications in human and mouse. Cell. 2005;120:169–181.
- Bonasio R, Tu S, Reinberg D. Molecular signals of epigenetic states. Science. 2010;330:612–616.
- Peters AH, et al. Partitioning and plasticity of repressive histone methylation states in mammalian chromatin. Mol Cell. 2003;12:1577–1589.
- Heintzman ND, et al. Histone modifications at human enhancers reflect global cell-type-specific gene expression. Nature. 2009;459:108–112.
- Rada-Iglesias A, et al. A unique chromatin signature uncovers early developmental enhancers in humans. Nature. 2011;470:279–283.
- Creyghton MP, et al. Histone H3K27ac separates active from poised enhancers and predicts developmental state. Proc Natl Acad Sci U S A. 2010;107:21931–21936.
- Cedar H, Bergman Y. Linking DNA methylation and histone modification: patterns and paradigms. Nat Rev Genet. 2009;10:295–304.
- Stevens M, et al. Estimating absolute methylation levels at single-CpG resolution from methylation enrichment and restriction enzyme sequencing methods. Genome Res. 2013;23:1541–1553.
- Zhang Y, et al. Model-based analysis of ChIP-Seq (MACS). Genome Biol. 2008;9:R137.
- Butterfield YS, et al. JAGuaR: Junction Alignments to Genome for RNA-Seq Reads. PLoS One. 2014;9:e102398.
- Coarfa C, et al. Pash 3.0: A versatile software package for read mapping and integrative analysis of genomic and epigenomic variation using massively parallel DNA sequencing. BMC Bioinformatics. 2010;11:572.
- Li H, Durbin R. Fast and accurate short read alignment with Burrows-Wheeler transform. Bioinformatics. 2009;25:1754–1760.
- Fejes AP, et al. FindPeaks 3.1: a tool for identifying areas of enrichment from massively parallel short-read sequencing technology. Bioinformatics. 2008;24:1729–1730.
- Landt SG, et al. ChIP-seq guidelines and practices of the ENCODE and modENCODE consortia. Genome Res. 2012;22:1813–1831.
- Kunde-Ramamoorthy G, et al. Comparison and quantitative verification of mapping algorithms for whole-genome bisulfite sequencing. Nucleic Acids Res. 2014;42:e43.
- Harris RA, et al. Comparison of sequencing-based methods to profile DNA methylation and identification of monoallelic epigenetic modifications. Nat Biotechnol. 2010;28:1097–1105.
- Ernst J, Kellis M. Discovery and characterization of chromatin states for systematic annotation of the human genome. Nat Biotechnol. 2010;28:817–825.
- Davydov EV, et al. Identifying a high fraction of the human genome to be under selective constraint using GERP++. PLoS Comput Biol. 2010;6:e1001025.
- Kagey MH, et al. Mediator and cohesin connect gene expression and chromatin architecture. Nature. 2010;467:430–435.
- Stadler MB, et al. DNA-binding factors shape the mouse methylome at distal regulatory regions. Nature. 2011;480:490–495.
- Gascard P, et al. Epigenetic and transcriptional determinants of mammary gland development. Companion Manuscript. 2015
- Mohn F, Weber M, Schubeler D, Roloff TC. Methylated DNA immunoprecipitation (MeDIP). Methods Mol Biol. 2009;507:55–64.
- Elliott G, et al. Intermediate DNA Methylation is a Conserved Signature of Genome Regulation. Companion Manuscript. 2015
- Ji H, et al. Comprehensive methylome map of lineage commitment from haematopoietic progenitors. Nature. 2010;467:338–342.
- Meissner A, et al. Genome-scale DNA methylation maps of pluripotent and differentiated cells. Nature. 2008;454:766–770.
- Gifford CA, et al. Transcriptional and epigenetic dynamics during specification of human embryonic stem cells. Cell. 2013;153:1149–1163.
- Ziller MJ, et al. Charting a dynamic DNA methylation landscape of the human genome. Nature. 2013;500:477–481.
- Tsankov AM, et al. Modular and context dependent rewiring of transcription factor networks during human ESC differentiation. Companion Manuscript. 2015
- Ziller MJ, et al. Dissecting neural differentiation regulatory networks through epigenetic footprinting. Nature. 2014
- Xie M, et al. DNA hypomethylation within specific transposable element families associates with tissue-specific enhancer landscape. Nat Genet. 2013;45:836–841.
- McLean CY, et al. GREAT improves functional interpretation of cis-regulatory regions. Nat Biotechnol. 2010;28:495–501.
- Lowdon RF, et al. Regulatory network decoded from epigenomes of surface ectoderm-derived cell types. Nat Commun. 2014;5:5442.
- Amin V, et al. Epigenomic footprints across 111 reference epigenomes reveal tissue-specific epigenetic regulation of lincRNAs. Nature Communications. 2015
- Bernstein BE, et al. A bivalent chromatin structure marks key developmental genes in embryonic stem cells. Cell. 2006;125:315–326.
- Hawkins RD, et al. Distinct epigenomic landscapes of pluripotent and lineage-committed human cells. Cell Stem Cell. 2010;6:479–491.
- Varley KE, et al. Dynamic DNA methylation across diverse human cell lines and tissues. Genome Res. 2013;23:555–567.
- Leung D, et al. Integrative analysis of haplotype-resolved epigenomes across human tissues. Companion Manuscript. 2015
- Lieberman-Aiden E, et al. Comprehensive mapping of long-range interactions reveals folding principles of the human genome. Science. 2009;326:289–293.
- Meuleman W, et al. Constitutive nuclear lamina-genome interactions are highly conserved and associated with A/T-rich sequence. Genome Res. 2013;23:270–280.
- Guelen L, et al. Domain organization of human chromosomes revealed by mapping of nuclear lamina interactions. Nature. 2008;453:948–951.
- Antequera F, Boyes J, Bird A. High levels of de novo methylation and altered chromatin structure at CpG islands in cell lines. Cell. 1990;62:503–514.
- Ashburner M, et al. Gene ontology: tool for the unification of biology. The Gene Ontology Consortium. Nat Genet. 2000;25:25–29.
- Kohler S, et al. The Human Phenotype Ontology project: linking molecular biology and disease through phenotype data. Nucleic Acids Res. 2014;42:D966–974.
- Kheradpour P, Kellis M. Systematic discovery and characterization of regulatory motifs in ENCODE TF binding experiments. Nucleic Acids Res. 2014;42:2976–2987.
- Hesselberth JR, et al. Global mapping of protein-DNA interactions in vivo by digital genomic footprinting. Nat Methods. 2009;6:283–289.
- Kheradpour P, Stark A, Roy S, Kellis M. Reliable prediction of regulator targets using 12 Drosophila genomes. Genome Res. 2007;17:1919–1931.
- Whitaker JW, Chen Z, Wang W. Predicting the human epigenome from DNA motifs. Nat Methods. 2014
- Dixon JR, et al. Global Reorganization of Chromatin Architecture during Embryonic Stem Cell Differentiation. Companion Manuscript. 2015
- Lindblad-Toh K, et al. A high-resolution map of human evolutionary constraint using 29 mammals. Nature. 2011;478:476–482.
- Trynka G, et al. Chromatin marks identify critical cell types for fine mapping complex trait variants. Nat Genet. 2013;45:124–130.
- Welter D, et al. The NHGRI GWAS Catalog, a curated resource of SNP-trait associations. Nucleic Acids Res. 2014;42:D1001–1006.
- Franke A, et al. Genome-wide meta-analysis increases to 71 the number of confirmed Crohn's disease susceptibility loci. Nat Genet. 2010;42:1118–1125.
- Cooper JD, et al. Meta-analysis of genome-wide association study data identifies additional type 1 diabetes risk loci. Nat Genet. 2008;40:1399–1401.
- Berndt SI, et al. Genome-wide association study identifies multiple risk loci for chronic lymphocytic leukemia. Nat Genet. 2013;45:868–876.
- Stahl EA, et al. Genome-wide association study meta-analysis identifies seven new rheumatoid arthritis risk loci. Nat Genet. 2010;42:508–514.
- Barrett JC, et al. Genome-wide association study and meta-analysis find that over 40 loci affect risk of type 1 diabetes. Nat Genet. 2009;41:703–707.
- Jostins L, et al. Host-microbe interactions have shaped the genetic architecture of inflammatory bowel disease. Nature. 2012;491:119–124.
- Yang W, et al. Meta-analysis followed by replication identifies loci in or near CDKN1B, TET3, CD80, DRAM1, and ARID5B as associated with systemic lupus erythematosus in Asians. Am J Hum Genet. 2013;92:41–51.
- Musunuru K, et al. From noncoding variant to phenotype via SORT1 at the 1p13 cholesterol locus. Nature. 2010;466:714–719.
- Willy PJ, et al. LXR, a nuclear receptor that defines a distinct retinoid response pathway. Genes Dev. 1995;9:1033–1045.
- Pasquali L, et al. Pancreatic islet enhancer clusters enriched in type 2 diabetes risk-associated variants. Nat Genet. 2014;46:136–143.
- Dalcik H, et al. Expression of insulin-like growth factor in the placenta of intrauterine growth- retarded human fetuses. Acta Histochem. 2001;103:195–207.
- Lesch KP, et al. Molecular genetics of adult ADHD: converging evidence from genome-wide association and extended pedigree linkage studies. J Neural Transm. 2008;115:1573–1585.
- Repunte-Canonigo V, et al. A potential role for adiponectin receptor 2 (AdipoR2) in the regulation of alcohol intake. Brain Res. 2010;1339:11–17.
- Sawcer S, et al. Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis. Nature. 2011;476:214–219.
- Heneka MT, Kummer MP, Latz E. Innate immune activation in neurodegenerative disease. Nat Rev Immunol. 2014;14:463–477.
- Gjoneska E, Pfenning AR, Kundaje A, Tsai L-H, Kellis M. Conserved epigenomic signatures between mouse and human elucidate immune basis of Alzheimer's disease. Nature, Companion Manuscript. 2015
- Zhou X, et al. Epigenomic annotation of genetic variants using the Roadmap EpiGenome Browser. Nat Biotechnol. 2015
- Ward LD, Kellis M. HaploReg: a resource for exploring chromatin states, conservation, and regulatory motif alterations within sets of genetically linked variants. Nucleic Acids Res. 2012;40:D930–934.
- Satterlee JS, Schubeler D, Ng HH. Tackling the epigenome: challenges and opportunities for collaboration. Nat Biotechnol. 2010;28:1039–1044.
- Farh KK, et al. Genetic and epigenetic fine mapping of causal autoimmune disease variants. Nature. 2014
- Seumois G, et al. Epigenomic analysis of primary human T cells reveals enhancers associated with TH2 memory cell differentiation and asthma susceptibility. Nat Immunol. 2014;15:777–788.
- De Jager PL, et al. Alzheimer's disease: early alterations in brain DNA methylation at ANK1, BIN1, RHBDF2 and other loci. Nat Neurosci. 2014;17:1156–1163.
- Lunnon K, et al. Methylomic profiling implicates cortical deregulation of ANK1 in Alzheimer's disease. Nat Neurosci. 2014;17:1164–1170.
- Polak P, et al. Cell type of origin chromatin organization shapes the mutational landscape of cancer. Companion Manuscript. 2015
- Yao L, Tak YG, Berman BP, Farnham PJ. Functional annotation of colon cancer risk SNPs. Nat Commun. 2014;5:5114.
- Zhou X, et al. The Human Epigenome Browser at Washington University. Nat Methods. 2011;8:989–990.
- Karolchik D, et al. The UCSC Genome Browser Database. Nucleic Acids Res. 2003;31:51–54.
- Chadwick LH. The NIH Roadmap Epigenomics Program data resource. Epigenomics. 2012;4:317–324.
- John S, et al. Chromatin accessibility pre-determines glucocorticoid receptor binding patterns. Nat Genet. 2011;43:264–268.
- Ernst J, Kellis M. Interplay between chromatin state, regulator binding, and regulatory motifs in six human cell types. Genome Res. 2013;23:1142–1154.
- Ernst J, Kellis M. ChromHMM: automating chromatin-state discovery and characterization. Nat Methods. 2012;9:215–216.
- Dixon JR, et al. Topological domains in mammalian genomes identified by analysis of chromatin interactions. Nature. 2012;485:376–380.
- Lister R, et al. Global epigenomic reconfiguration during mammalian brain development. Science. 2013;341:1237905.
- Schultz MD, Schmitz RJ, Ecker JR. 'Leveling' the playing field for analyses of single-base resolution DNA methylomes. Trends Genet. 2012;28:583–585.
- Bar-Joseph Z, Gifford DK, Jaakkola TS. Fast optimal leaf ordering for hierarchical clustering. Bioinformatics. 2001;17(Suppl 1):S22–29.
- Leisch F. A toolbox for KK-centroids cluster analysis. Computational Statistics and Data Analysis. 2006 .
- Matys V, et al. TRANSFAC: transcriptional regulation, from patterns to profiles. Nucleic Acids Res. 2003;31:374–378.
- Sandelin A, Alkema W, Engstrom P, Wasserman WW, Lenhard B. JASPAR: an open-access database for eukaryotic transcription factor binding profiles. Nucleic Acids Res. 2004;32:D91–94.
- Berger MF, et al. Compact, universal DNA microarrays to comprehensively determine transcription-factor binding site specificities. Nat Biotechnol. 2006;24:1429–1435.
- Berger MF, et al. Variation in homeodomain DNA binding revealed by high-resolution analysis of sequence preferences. Cell. 2008;133:1266–1276.
- Jolma A, et al. DNA-binding specificities of human transcription factors. Cell. 2013;152:327–339.
- Badis G, et al. Diversity and complexity in DNA recognition by transcription factors. Science. 2009;324:1720–1723.
- Shannon P, et al. Cytoscape: a software environment for integrated models of biomolecular interaction networks. Genome Res. 2003;13:2498–2504.
- Karolchik D, et al. The UCSC Table Browser data retrieval tool. Nucleic Acids Res. 2004;32:D493–496.
- Garber M, et al. Identifying novel constrained elements by exploiting biased substitution patterns. Bioinformatics. 2009;25:i54–62.
- Osborne JD, et al. Annotating the human genome with Disease Ontology. BMC Genomics. 2009;10(Suppl 1):S6.
- Hill DP, et al. The mouse Gene Expression Database (GXD): updates and enhancements. Nucleic Acids Res. 2004;32:D568–571.
Source: PubMed