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Mol Cell. 2014 Oct 23;56(2):286-297. doi: 10.1016/j.molcel.2014.08.026. Epub 2014 Sep 25.

5mC oxidation by Tet2 modulates enhancer activity and timing of transcriptome reprogramming during differentiation.

Author information

1
Ludwig Institute for Cancer Research, La Jolla, CA 92093-0653, USA.
2
Department of Chemistry and Institute for Biophysical Dynamics, Howard Hughes Medical Institute, The University of Chicago, Chicago, IL 60637, USA.
3
State Key Laboratory of Molecular Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
4
Department of Chemistry and Institute for Biophysical Dynamics, Howard Hughes Medical Institute, The University of Chicago, Chicago, IL 60637, USA. Electronic address: chuanhe@uchicago.edu.
5
Ludwig Institute for Cancer Research, La Jolla, CA 92093-0653, USA; Department of Cellular and Molecular Medicine, Institute of Genomic Medicine, and Moores Cancer Center, University of California, San Diego School of Medicine, La Jolla, CA 92093. Electronic address: biren@ucsd.edu.

Abstract

In mammals, cytosine methylation (5mC) is widely distributed throughout the genome but is notably depleted from active promoters and enhancers. While the role of DNA methylation in promoter silencing has been well documented, the function of this epigenetic mark at enhancers remains unclear. Recent experiments have demonstrated that enhancers are enriched for 5-hydroxymethylcytosine (5hmC), an oxidization product of the Tet family of 5mC dioxygenases and an intermediate of DNA demethylation. These results support the involvement of Tet proteins in the regulation of dynamic DNA methylation at enhancers. By mapping DNA methylation and hydroxymethylation at base resolution, we find that deletion of Tet2 causes extensive loss of 5hmC at enhancers, accompanied by enhancer hypermethylation, reduction of enhancer activity, and delayed gene induction in the early steps of differentiation. Our results reveal that DNA demethylation modulates enhancer activity, and its disruption influences the timing of transcriptome reprogramming during cellular differentiation.

PMID:
25263596
PMCID:
PMC4319980
DOI:
10.1016/j.molcel.2014.08.026
[Indexed for MEDLINE]
Free PMC Article

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