Charting a dynamic DNA methylation landscape of the human genome
Open accessAbstract
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.
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Dynamically methylated CpGs cluster into more than one million tissue-specific differentially methylated regions.
“These dynamically methylated CpGs cluster into over 1 million tissue specific differentially methylated regions (DMRs).”
From Dynamic DNA methylation: In the right place at the right time (2018) · cites this paper as [5]
Under normal physiological conditions, 15% to 21% of CpGs differ in methylation status between human tissues.
“direct comparison of whole genome methylome profiles derived from numerous cell types has revealed that under normal physiological conditions 15%-21% of CpGs vary in methylation status between human tissues (4, 5).”
From Dynamic DNA methylation: In the right place at the right time (2018) · cites this paper as [5]
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- Authors
- Ziller, M. J., Gu, H., Müller, F., Donaghey, J., Tsai, L. T.-Y., Kohlbacher, O., De Jager, P. L., Rosen, E. D., Bennett, D. A., Bernstein, B. E., Gnirke, A., & Meissner, A.
- Affiliations
- Broad Institute (US)
- Harvard University (US)
- Beth Israel Deaconess Medical Center (US)
- Quantitative Biology Center (DE)
- Rush University Medical Center (US)
- Corresponding author
- Meissner, Alexander
- ORCID
- Venue
- Nature
- Published
- 2013-08
- Volume
- 500
- Issue
- 7463
- Pages
- 477-481
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC3821869
- OpenAlex
- W2163327652
- Cited by
- 1,357
- References
- 30
- Citations by year
- 2026: 48 · 2025: 42 · 2024: 99 · 2023: 74 · 2022: 112 · 2021: 97 · 2020: 91 · 2019: 103 · 2018: 100 · 2017: 128 · 2016: 151 · 2015: 159 · 2014: 133 · 2013: 17
- FWCI
- 68.63
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- MPG.PuRe (Max Planck Society) (submittedVersion, other-oa)
- Digital Access to Scholarship at Harvard (DASH) (Harvard University) (submittedVersion, cc-by)
- RePEc: Research Papers in Economics (submittedVersion)
- Max Planck Digital Library (submittedVersion, other-oa)
- Funders
- National Institute on Aging (R01AG017917, R01AG36042, P30-AG 10161, R01‐AG17917, R01 AG15819, R01AG036042, R01AG015819, P30AG010161, RF1AG036042)
- National Institute of General Medical Sciences (P01GM099117)
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK087092)
- National Institute of Environmental Health Sciences (U01ES017155, ES017690)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Syndromes and Imprinting
- Keywords
- CpG methylation, cell type-specific methylation, differentially methylated regions, enhancers, transcription factor binding sites, gene regulatory elements, single nucleotide polymorphisms, epigenetic regulation, bisulfite sequencing, epigenome mapping
- MeSH terms
- Binding Sites, Enhancer Elements, Genetic, Humans, Organ Specificity, Sulfites, Transcription Factors, Genome, Human, Sequence Analysis, DNA, CpG Islands, DNA Methylation, Polymorphism, Single Nucleotide, Genome-Wide Association Study
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