Journal
NATURE STRUCTURAL & MOLECULAR BIOLOGY
Volume 25, Issue 4, Pages 327-+Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/s41594-018-0046-4
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Funding
- Ford Foundation
- UNCF/Merck Science Initiative
- Harvard Medical School
- Broad Institute Diversity Initiative
- Les Turner ALS Foundation
- Muscular Dystrophy Association
- Feinberg School of Medicine
- Max Planck Society
- New York Stem Cell Foundation
- Broad Institute (SPARC)
- NIH [1P50HG006193, P01GM099117, R01DA036898]
- NATIONAL HUMAN GENOME RESEARCH INSTITUTE [RM1HG006193, P50HG006193] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES [P01GM099117] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE ON DRUG ABUSE [R01DA036898] Funding Source: NIH RePORTER
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Cytosine methylation is widespread among organisms and essential for mammalian development. In line with early postulations of an epigenetic role in gene regulation, symmetric CpG methylation can be mitotically propagated over many generations with extraordinarily high fidelity. Here, we combine BrdU labeling and immunoprecipitation with genome-wide bisulfite sequencing to explore the inheritance of cytosine methylation onto newly replicated DNA in human cells. Globally, we observe a pronounced lag between the copying of genetic and epigenetic information in embryonic stem cells that is reconsolidated within hours to accomplish faithful mitotic transmission. Populations of arrested cells show a global reduction of lag-induced intermediate CpG methylation when compared to proliferating cells, whereas sites of transcription factor engagement appear cell-cycle invariant. Alternatively, the cancer cell line HCT116 preserves global epigenetic heterogeneity independently of cellcycle arrest. Taken together, our data suggest that heterogeneous methylation largely reflects asynchronous proliferation, but is intrinsic to actively engaged cis-regulatory elements and cancer.
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