Locus- and cell type-specific epigenetic switching during cellular differentiation in mammals

Abstract

BACKGROUND: Epigenomic reconfiguration, including changes in DNA methylation and histone modifications, is crucial for the differentiation of embryonic stem cells (ESCs) into somatic cells. However, the extent to which the epigenome is reconfigured and the interplay between components of the epigenome during cellular differentiation remain poorly defined.

METHODS: We systematically analyzed and compared DNA methylation, various histone modification, and transcriptome profiles in ESCs with those of two distinct types of somatic cells from human and mouse.

RESULTS: We found that global DNA methylation levels are lower in somatic cells compared to ESCs in both species. We also found that 80% of regions with histone modification occupancy differ between human ESCs and the two human somatic cell types. Approximately 70% of the reconfigurations in DNA methylation and histone modifications are locus- and cell type-specific. Intriguingly, the loss of DNA methylation is accompanied by the gain of different histone modifications in a locus- and cell type-specific manner. Further examination of transcriptional changes associated with epigenetic reconfiguration at promoter regions revealed an epigenetic switching for gene regulation—a transition from stable gene silencing mediated by DNA methylation in ESCs to flexible gene repression facilitated by repressive histone modifications in somatic cells.

CONCLUSIONS: Our findings demonstrate that the epigenome is reconfigured in a locus- and cell type-specific manner and epigenetic switching is common during cellular differentiation in both human and mouse.

Key words： DNA methylation; histone modifications; epigenome; epigenetic switch; cellular differentiation

Acknowledgements

We thank members of the Zhou laboratory for discussions and comments and the ENCODE Consortium and NIH Roadmap Epigenomics Mapping Consortium for availability of data sets. This work was funded by grants from the National Institutes of Health (R01MH091850 to Z.Z.), and Z.Z. is a Pew scholar in biomedical sciences.

Compliance with ethics guidelines

Ying-Tao Zhao, Maria Fasolino and Zhaolan Zhou declares that they have no conflict of interest. This article does not contain any studies with human or animal subjects performed by any of the authors.

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