Dynamic DNA methylation across diverse human cell lines and tissues

被引:523
作者
Varley, Katherine E. [1 ]
Gertz, Jason [1 ]
Bowling, Kevin M. [1 ]
Parker, Stephanie L. [1 ]
Reddy, Timothy E. [1 ]
Pauli-Behn, Florencia [1 ]
Cross, Marie K. [1 ]
Williams, Brian A. [2 ,3 ]
Stamatoyannopoulos, John A. [4 ,5 ]
Crawford, Gregory E. [6 ,7 ]
Absher, Devin M. [1 ]
Wold, Barbara J. [2 ,3 ]
Myers, Richard M. [1 ]
机构
[1] HudsonAlpha Inst Biotechnol, Huntsville, AL 35806 USA
[2] CALTECH, Div Biol, Pasadena, CA 91125 USA
[3] CALTECH, Beckman Inst, Pasadena, CA 91125 USA
[4] Univ Washington, Dept Genome Sci, Seattle, WA 98195 USA
[5] Univ Washington, Dept Med, Seattle, WA 98195 USA
[6] Duke Univ, Dept Pediat, Durham, NC 27708 USA
[7] Duke Univ, Inst Genome Sci & Policy, Durham, NC 27708 USA
关键词
TUMOR PROGRESSION; CANCER; GENE; CHROMATIN; PHENOTYPE; METHYLOME; HYPERMETHYLATION; SIGNATURE; SEQUENCE; DIFFERENTIATION;
D O I
10.1101/gr.147942.112
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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.
引用
收藏
页码:555 / 567
页数:13
相关论文
共 69 条
[1]   FOXD3 Is a Mutant B-RAF-Regulated Inhibitor of G1-S Progression in Melanoma Cells [J].
Abel, Ethan V. ;
Aplin, Andrew E. .
CANCER RESEARCH, 2010, 70 (07) :2891-2900
[2]   Replication timing-related and gene body-specific methylation of active human genes [J].
Aran, Dvir ;
Toperoff, Gidon ;
Rosenberg, Michael ;
Hellman, Asaf .
HUMAN MOLECULAR GENETICS, 2011, 20 (04) :670-680
[3]   Targeted and genome-scale strategies reveal gene-body methylation signatures in human cells [J].
Ball, Madeleine P. ;
Li, Jin Billy ;
Gao, Yuan ;
Lee, Je-Hyuk ;
LeProust, Emily M. ;
Park, In-Hyun ;
Xie, Bin ;
Daley, George Q. ;
Church, George M. .
NATURE BIOTECHNOLOGY, 2009, 27 (04) :361-368
[4]   An embryonic stem cell-like gene expression signature in poorly differentiated aggressive human tumors [J].
Ben-Porath, Ittai ;
Thomson, Matthew W. ;
Carey, Vincent J. ;
Ge, Ruping ;
Bell, George W. ;
Regev, Aviv ;
Weinberg, Robert A. .
NATURE GENETICS, 2008, 40 (05) :499-507
[5]   Regions of focal DNA hypermethylation and long-range hypomethylation in colorectal cancer coincide with nuclear lamina-associated domains [J].
Berman, Benjamin P. ;
Weisenberger, Daniel J. ;
Aman, Joseph F. ;
Hinoue, Toshinori ;
Ramjan, Zachary ;
Liu, Yaping ;
Noushmehr, Houtan ;
Lange, Christopher P. E. ;
van Dijk, Cornelis M. ;
Tollenaar, Rob A. E. M. ;
Van den Berg, David ;
Laird, Peter W. .
NATURE GENETICS, 2012, 44 (01) :40-U62
[6]   Identification and analysis of functional elements in 1% of the human genome by the ENCODE pilot project [J].
Birney, Ewan ;
Stamatoyannopoulos, John A. ;
Dutta, Anindya ;
Guigo, Roderic ;
Gingeras, Thomas R. ;
Margulies, Elliott H. ;
Weng, Zhiping ;
Snyder, Michael ;
Dermitzakis, Emmanouil T. ;
Stamatoyannopoulos, John A. ;
Thurman, Robert E. ;
Kuehn, Michael S. ;
Taylor, Christopher M. ;
Neph, Shane ;
Koch, Christoph M. ;
Asthana, Saurabh ;
Malhotra, Ankit ;
Adzhubei, Ivan ;
Greenbaum, Jason A. ;
Andrews, Robert M. ;
Flicek, Paul ;
Boyle, Patrick J. ;
Cao, Hua ;
Carter, Nigel P. ;
Clelland, Gayle K. ;
Davis, Sean ;
Day, Nathan ;
Dhami, Pawandeep ;
Dillon, Shane C. ;
Dorschner, Michael O. ;
Fiegler, Heike ;
Giresi, Paul G. ;
Goldy, Jeff ;
Hawrylycz, Michael ;
Haydock, Andrew ;
Humbert, Richard ;
James, Keith D. ;
Johnson, Brett E. ;
Johnson, Ericka M. ;
Frum, Tristan T. ;
Rosenzweig, Elizabeth R. ;
Karnani, Neerja ;
Lee, Kirsten ;
Lefebvre, Gregory C. ;
Navas, Patrick A. ;
Neri, Fidencio ;
Parker, Stephen C. J. ;
Sabo, Peter J. ;
Sandstrom, Richard ;
Shafer, Anthony .
NATURE, 2007, 447 (7146) :799-816
[7]   Epigenetic specificity of loss of imprinting of the IGF2 gene in Wilms tumors [J].
Bjornsson, Hans T. ;
Brown, Lindsey J. ;
Fallin, M. Danielle ;
Rongione, Michael A. ;
Bibikova, Marina ;
Wickham, Eliza ;
Fan, Jian-Bing ;
Feinberg, Andrew P. .
JNCI-JOURNAL OF THE NATIONAL CANCER INSTITUTE, 2007, 99 (16) :1270-1273
[8]   Reprogramming efficiency following somatic cell nuclear transfer is influenced by the differentiation and methylation state of the donor nucleus [J].
Blelloch, Robert ;
Wang, Zhongde ;
Meissner, Alex ;
Pollard, Steven ;
Smith, Austin ;
Jaenisch, Rudolf .
STEM CELLS, 2006, 24 (09) :2007-2013
[9]   Sequential ChIP-bisulfite sequencing enables direct genome-scale investigation of chromatin and DNA methylation cross-talk [J].
Brinkman, Arie B. ;
Gu, Hongcang ;
Bartels, Stefanie J. J. ;
Zhang, Yingying ;
Matarese, Filomena ;
Simmer, Femke ;
Marks, Hendrik ;
Bock, Christoph ;
Gnirke, Andreas ;
Meissner, Alexander ;
Stunnenberg, Hendrik G. .
GENOME RESEARCH, 2012, 22 (06) :1128-1138
[10]   High CpG island methylator phenotype is associated with lymph node metastasis and prognosis in gastric cancer [J].
Chen, Hua-Yun ;
Zhu, Bao-He ;
Zhang, Chang-Hua ;
Yang, Dong-Jie ;
Peng, Jian-Jun ;
Chen, Jian-Hui ;
Liu, Fa-Keng ;
He, Yu-Long .
CANCER SCIENCE, 2012, 103 (01) :73-79