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Published March 2013 | Published + Supplemental Material
Journal Article Open

Dynamic DNA methylation across diverse human cell lines and tissues


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.

Additional Information

© 2013 Published by Cold Spring Harbor Laboratory Press. Received August 16, 2012; accepted in revised form November 21, 2012. Published in Advance January 16, 2013. This work was supported by NHGRI grant number U54 HG004576 to R.M.M. and B.J.W. as part of The ENCODE Project. We thank members of the Pritzker Neuropsychiatric Disorders Research Consortium, particularly Drs. William Bunney, Edward Jones (deceased), Huda Akil, Stan Watson, Alan Schatzberg, and Jack Barchas for providing the 24 post-mortem brain tissues for validating the non-CpG methylation that we discovered in this study, and J.D. Frey for his assistance with figure illustrations.

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Published - Genome_Res.-2013-Varley-555-67.pdf

Supplemental Material - Supp_Figures.doc

Supplemental Material - Supp_Tables.xls


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