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Nature DOI:10.1038/nature12433

Charting a dynamic DNA methylation landscape of the human genome.

Publication TypeJournal Article
Year of Publication2013
AuthorsZiller, MJ, Gu, H, Müller, F, Donaghey, J, Tsai, LT-Y, Kohlbacher, O, De Jager, PL, Rosen, ED, Bennett, DA, Bernstein, BE, Gnirke, A, Meissner, A
Date Published2013 Aug 22
KeywordsBinding Sites, CpG Islands, DNA Methylation, Enhancer Elements, Genetic, Genome, Human, Genome-Wide Association Study, Humans, Organ Specificity, Polymorphism, Single Nucleotide, Sequence Analysis, DNA, Sulfites, Transcription Factors

DNA methylation is a defining feature of mammalian cellular identity and is essential for normal development. Most cell types, except germ cells and pre-implantation embryos, display relatively stable DNA methylation patterns, with 70-80% of all CpGs being methylated. Despite recent advances, we still have a limited understanding of when, where and how many CpGs participate in genomic regulation. Here we report the in-depth analysis of 42 whole-genome bisulphite sequencing data sets across 30 diverse human cell and tissue types. We observe dynamic regulation for only 21.8% of autosomal CpGs within a normal developmental context, most of which are distal to transcription start sites. These dynamic CpGs co-localize with gene regulatory elements, particularly enhancers and transcription-factor-binding sites, which allow identification of key lineage-specific regulators. In addition, differentially methylated regions (DMRs) often contain single nucleotide polymorphisms associated with cell-type-related diseases as determined by genome-wide association studies. The results also highlight the general inefficiency of whole-genome bisulphite sequencing, as 70-80% of the sequencing reads across these data sets provided little or no relevant information about CpG methylation. To demonstrate further the utility of our DMR set, we use it to classify unknown samples and identify representative signature regions that recapitulate major DNA methylation dynamics. In summary, although in theory every CpG can change its methylation state, our results suggest that only a fraction does so as part of coordinated regulatory programs. Therefore, our selected DMRs can serve as a starting point to guide new, more effective reduced representation approaches to capture the most informative fraction of CpGs, as well as further pinpoint putative regulatory elements.


Alternate JournalNature
PubMed ID23925113
PubMed Central IDPMC3821869
Grant ListR01AG36042 / AG / NIA NIH HHS / United States
P01 GM099117 / GM / NIGMS NIH HHS / United States
U01ES017155 / ES / NIEHS NIH HHS / United States
R01 AG017917 / AG / NIA NIH HHS / United States
R01AG17917 / AG / NIA NIH HHS / United States
P01GM099117 / GM / NIGMS NIH HHS / United States
R01AG15819 / AG / NIA NIH HHS / United States
ES017690 / ES / NIEHS NIH HHS / United States
P30AG10161 / AG / NIA NIH HHS / United States
U01 ES017155 / ES / NIEHS NIH HHS / United States