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Mol Cell. 2015 Nov 19;60(4):584-96. doi: 10.1016/j.molcel.2015.10.025.

H3K4/H3K9me3 Bivalent Chromatin Domains Targeted by Lineage-Specific DNA Methylation Pauses Adipocyte Differentiation.

Author information

1
Division of Metabolic Medicine, The University of Tokyo, 4-6-1, Komaba, Meguro-ku, Tokyo 153-8904, Japan; The Translational Systems Biology and Medicine Initiative (TSBMI), Center for Disease Biology and Integrative Medicine, Faculty of Medicine, The University of Tokyo, Tokyo 113-8655, Japan. Electronic address: matsumura-y@lsbm.org.
2
Genome Science Division, The University of Tokyo, 4-6-1, Komaba, Meguro-ku, Tokyo 153-8904, Japan.
3
Division of Metabolic Medicine, The University of Tokyo, 4-6-1, Komaba, Meguro-ku, Tokyo 153-8904, Japan; The Translational Systems Biology and Medicine Initiative (TSBMI), Center for Disease Biology and Integrative Medicine, Faculty of Medicine, The University of Tokyo, Tokyo 113-8655, Japan.
4
Division of Metabolic Medicine, The University of Tokyo, 4-6-1, Komaba, Meguro-ku, Tokyo 153-8904, Japan; Laboratory of Genome and Biosignals, Tokyo University of Pharmacy and Life Science, Tokyo 192-0392, Japan.
5
Division of Metabolic Medicine, The University of Tokyo, 4-6-1, Komaba, Meguro-ku, Tokyo 153-8904, Japan.
6
Department of Biological Sciences, Graduate School of Bioscience and Biotechnology, Tokyo Institute of Technology, Yokohama 226-8501, Japan.
7
Division of Metabolic Medicine, The University of Tokyo, 4-6-1, Komaba, Meguro-ku, Tokyo 153-8904, Japan; Laboratory for Systems Biology and Medicine, Research Center for Advanced Science and Technology, The University of Tokyo, 4-6-1, Komaba, Meguro-ku, Tokyo 153-8904, Japan; The Translational Systems Biology and Medicine Initiative (TSBMI), Center for Disease Biology and Integrative Medicine, Faculty of Medicine, The University of Tokyo, Tokyo 113-8655, Japan.
8
Department of Medical Cell Biology, Institute of Molecular Embryology and Genetics, Kumamoto University, Kumamoto 860-0811, Japan.
9
Graduate School of Pharmaceutical Sciences, Osaka University, Suita, Osaka 565-0871, Japan.
10
Laboratory of Genome and Biosignals, Tokyo University of Pharmacy and Life Science, Tokyo 192-0392, Japan.
11
Metabolic Disease Program, Sanford-Burnham Medical Research Institute, Orlando, FL 32827, USA.
12
Laboratory for Systems Biology and Medicine, Research Center for Advanced Science and Technology, The University of Tokyo, 4-6-1, Komaba, Meguro-ku, Tokyo 153-8904, Japan.
13
Genome Science Division, The University of Tokyo, 4-6-1, Komaba, Meguro-ku, Tokyo 153-8904, Japan; The Translational Systems Biology and Medicine Initiative (TSBMI), Center for Disease Biology and Integrative Medicine, Faculty of Medicine, The University of Tokyo, Tokyo 113-8655, Japan.
14
Division of Metabolic Medicine, The University of Tokyo, 4-6-1, Komaba, Meguro-ku, Tokyo 153-8904, Japan; The Translational Systems Biology and Medicine Initiative (TSBMI), Center for Disease Biology and Integrative Medicine, Faculty of Medicine, The University of Tokyo, Tokyo 113-8655, Japan. Electronic address: jmsakai-tky@umin.ac.jp.

Abstract

Bivalent H3K4me3 and H3K27me3 chromatin domains in embryonic stem cells keep active developmental regulatory genes expressed at very low levels and poised for activation. Here, we show an alternative and previously unknown bivalent modified histone signature in lineage-committed mesenchymal stem cells and preadipocytes that pairs H3K4me3 with H3K9me3 to maintain adipogenic master regulatory genes (Cebpa and Pparg) expressed at low levels yet poised for activation when differentiation is required. We show lineage-specific gene-body DNA methylation recruits H3K9 methyltransferase SETDB1, which methylates H3K9 immediately downstream of transcription start sites marked with H3K4me3 to establish the bivalent domain. At the Cebpa locus, this prevents transcription factor C/EBPβ binding, histone acetylation, and further H3K4me3 deposition and is associated with pausing of RNA polymerase II, which limits Cebpa gene expression and adipogenesis.

KEYWORDS:

DNA methylation; H3K27me3; H3K4me3; H3K9me3; Histone methylation; RNA polymerase II; adipogenesis; bivalent chromatin domains; epigenome; gene-body methylation; lineage commitment

PMID:
26590716
DOI:
10.1016/j.molcel.2015.10.025
[Indexed for MEDLINE]
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