Dynamic DNA methylation across diverse human cell lines and tissues
Katherine E. Varley,Jason Gertz,Kevin M. Bowling,Stephanie L. Parker,Timothy E. Reddy,Florencia Pauli-Behn,Marie K. Cross,Brian A. Williams,John A. Stamatoyannopoulos,Gregory E. Crawford,Devin Absher,Barbara J. Wold,Richard M. Myers +12 more
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TLDR
The relationship between methylation and expression is context-dependent, and it is found that CpG-rich enhancers bound by EP300 in the bodies of expressed genes are unmethylated despite the dense gene-body methylation surrounding them.Abstract:
As studies of DNA methylation increase in scope, it has become evident that methylation has a complex relationship with gene expression, plays an important role in defining cell types, and is disrupted in many diseases. We describe large-scale single-base resolution DNA methylation profiling on a diverse collection of 82 human cell lines and tissues using reduced representation bisulfite sequencing (RRBS). Analysis integrating RNA-seq and ChIP-seq data illuminates the functional role of this dynamic mark. Loci that are hypermethylated across cancer types are enriched for sites bound by NANOG in embryonic stem cells, which supports and expands the model of a stem/progenitor cell signature in cancer. CpGs that are hypomethylated across cancer types are concentrated in megabase-scale domains that occur near the telomeres and centromeres of chromosomes, are depleted of genes, and are enriched for cancer-specific EZH2 binding and H3K27me3 (repressive chromatin). In noncancer samples, there are cell-type specific methylation signatures preserved in primary cell lines and tissues as well as methylation differences induced by cell culture. The relationship between methylation and expression is context-dependent, and we find that CpG-rich enhancers bound by EP300 in the bodies of expressed genes are unmethylated despite the dense gene-body methylation surrounding them. Non-CpG cytosine methylation occurs in human somatic tissue, is particularly prevalent in brain tissue, and is reproducible across many individuals. This study provides an atlas of DNA methylation across diverse and well-characterized samples and enables new discoveries about DNA methylation and its role in gene regulation and disease.read more
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Integrative analysis of 111 reference human epigenomes
Anshul Kundaje,Wouter Meuleman,Wouter Meuleman,Jason Ernst,Misha Bilenky,Angela Yen,Angela Yen,Alireza Heravi-Moussavi,Pouya Kheradpour,Pouya Kheradpour,Zhizhuo Zhang,Zhizhuo Zhang,Jianrong Wang,Jianrong Wang,Michael J. Ziller,Viren Amin,John W. Whitaker,Matthew D. Schultz,Lucas D. Ward,Lucas D. Ward,Abhishek Sarkar,Abhishek Sarkar,Gerald Quon,Gerald Quon,Richard Sandstrom,Matthew L. Eaton,Matthew L. Eaton,Yi-Chieh Wu,Yi-Chieh Wu,Andreas R. Pfenning,Andreas R. Pfenning,Xinchen Wang,Xinchen Wang,Melina Claussnitzer,Melina Claussnitzer,Yaping Liu,Yaping Liu,Cristian Coarfa,R. Alan Harris,Noam Shoresh,Charles B. Epstein,Elizabeta Gjoneska,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,Mukul S. Bansal,Mukul S. Bansal,Annaick Carles,Jesse R. Dixon,Kai How Farh,Soheil Feizi,Soheil Feizi,Rosa Karlic,Ah Ram Kim,Ah Ram Kim,Ashwinikumar Kulkarni,Daofeng Li,Rebecca F. Lowdon,Ginell Elliott,Tim R. Mercer,Shane Neph,Vitor Onuchic,Paz Polak,Paz Polak,Nisha Rajagopal,Pradipta R. Ray,Richard C Sallari,Richard C Sallari,Kyle Siebenthall,Nicholas A Sinnott-Armstrong,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,Philip L. De Jager,Peggy J. Farnham,Susan J. Fisher,David Haussler,Steven J.M. Jones,Steven J.M. Jones,Wei Li,Marco A. Marra,Michael T. McManus,Shamil R. Sunyaev,Shamil R. Sunyaev,James A. Thomson,Thea D. Tlsty,Li-Huei Tsai,Li-Huei Tsai,Wei Wang,Robert A. Waterland,Michael Q. Zhang,Lisa Helbling Chadwick,Bradley E. Bernstein,Bradley E. Bernstein,Bradley E. Bernstein,Joseph F. Costello,Joseph R. Ecker,Martin Hirst,Alexander Meissner,Aleksandar Milosavljevic,Bing Ren,John A. Stamatoyannopoulos,Ting Wang,Manolis Kellis,Manolis Kellis +123 more
TL;DR: It is shown 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.
Integrative analysis of 111 reference human epigenomes
Anshul Kundaje,Wouter Meuleman,Jason Ernst,Angela Yen,Pouya Kheradpour,Zhizhuo Zhang,Jianrong Wang,Lucas D. Ward,Abhishek Sarkar,Gerald Quon,Matthew L. Eaton,Yi-Chieh Wu,Andreas R. Pfenning,Xinchen Wang,Melina Claussnitzer,Yaping Liu,Mukul S. Bansal,Soheil Feizi-Khankandi,Ah Ram Kim,Richard C Sallari,Nicholas A Sinnott-Armstrong,Laurie A. Boyer,Elizabeta Gjoneska,Li-Huei Tsai,Manolis Kellis +24 more
TL;DR: In this article, the authors describe the integrative analysis of 111 reference human epigenomes generated as part of the NIH Roadmap Epigenomics Consortium, profiled for histone modification patterns, DNA accessibility, DNA methylation and RNA expression.
Journal ArticleDOI
The accessible chromatin landscape of the human genome
Robert E. Thurman,Eric Rynes,Richard Humbert,Jeff Vierstra,Matthew T. Maurano,Eric Haugen,Nathan C. Sheffield,Andrew B. Stergachis,Hao Wang,Benjamin Vernot,Kavita Garg,Sam John,Richard Sandstrom,Daniel Bates,Lisa Boatman,Theresa K. Canfield,Morgan Diegel,Douglas Dunn,Abigail K. Ebersol,Tristan Frum,Erika Giste,Audra K. Johnson,Ericka M. Johnson,Tanya Kutyavin,Bryan R. Lajoie,Bum Kyu Lee,Kristen Lee,Darin London,Dimitra Lotakis,Shane Neph,Fidencio Neri,Eric D. Nguyen,Hongzhu Qu,Hongzhu Qu,Alex Reynolds,Vaughn Roach,Alexias Safi,Minerva E. Sanchez,Amartya Sanyal,Anthony Shafer,Jeremy M. Simon,Lingyun Song,Shinny Vong,Molly Weaver,Yongqi Yan,Zhancheng Zhang,Zhuzhu Zhang,Boris Lenhard,Muneesh Tewari,Michael O. Dorschner,R. Scott Hansen,Patrick A. Navas,George Stamatoyannopoulos,Vishwanath R. Iyer,Jason D. Lieb,Shamil R. Sunyaev,Joshua M. Akey,Peter J. Sabo,Rajinder Kaul,Terrence S. Furey,Job Dekker,Gregory E. Crawford,John A. Stamatoyannopoulos,John A. Stamatoyannopoulos +63 more
TL;DR: The first extensive map of human DHSs identified through genome-wide profiling in 125 diverse cell and tissue types is presented, revealing novel relationships between chromatin accessibility, transcription, DNA methylation and regulatory factor occupancy patterns.
Journal ArticleDOI
Global Epigenomic Reconfiguration During Mammalian Brain Development
Ryan Lister,Ryan Lister,Eran A. Mukamel,Joseph R. Nery,Mark A. Urich,Clare A. Puddifoot,Nicholas D. Johnson,Jacinta Lucero,Yun Huang,Andrew J. Dwork,Matthew D. Schultz,Matthew D. Schultz,Miao Yu,Julian Tonti-Filippini,Holger Heyn,Shijun Hu,Joseph C. Wu,Anjana Rao,Manel Esteller,Chuan He,Fatemeh Haghighi,Terrence J. Sejnowski,Terrence J. Sejnowski,M. Margarita Behrens,Joseph R. Ecker +24 more
TL;DR: The results extend the knowledge of the unique role of DNA methylation in brain development and function, and offer a new framework for testing the role of the epigenome in healthy function and in pathological disruptions of neural circuits.
Journal ArticleDOI
Charting a dynamic DNA methylation landscape of the human genome
Michael J. Ziller,Hongcang Gu,Fabian Müller,Julie Donaghey,Julie Donaghey,Linus T.-Y. Tsai,Oliver Kohlbacher,Philip L. De Jager,Philip L. De Jager,Evan D. Rosen,Evan D. Rosen,David A. Bennett,Bradley E. Bernstein,Bradley E. Bernstein,Andreas Gnirke,Alexander Meissner,Alexander Meissner +16 more
TL;DR: Although in theory every CpG can change its methylation state, the results suggest that only a fraction does so as part of coordinated regulatory programs, which highlights the general inefficiency of whole-genome bisulphite sequencing.
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