DNA methylation is a defining feature of mammalian cellular identity and is essential for normal development1,2. Most cell types, except germ cells and pre-implantation embryos3,4,5, display relatively stable DNA methylation patterns, with 70–80% of all CpGs being methylated6. 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.
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We would like to thank K. Clement, P. Samavarchi-Tehrani, Z. Smith, M. Chan and R. Karnik for discussions and feedback. We would also like to thank F. Kelley, T. Durham, C. Epstein, N. Shoresh, G. Lauwers and the Massachusetts General Hospital tissue repository for assisting in sample and data management. E.D.R. is supported by the National Institutes of Health (NIH) Roadmap Epigenomics Project (ES017690). D.A.B. is supported by NIH grants P30AG10161, R01AG17917, R01AG15819 and R01AG36042. A.M. is supported by the Pew Charitable Trusts and is a New York Stem Cell Foundation, Robertson Investigator. This work was funded by NIH grants (U01ES017155 and P01GM099117) and The New York Stem Cell Foundation.
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Population DNA methylation studies in the Developmental Origins of Health and Disease (DOHaD) framework
Journal of Developmental Origins of Health and Disease (2019)