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Nat Commun. 2018 Apr 11;9(1):1387. doi: 10.1038/s41467-018-03748-1.

Srf destabilizes cellular identity by suppressing cell-type-specific gene expression programs.

Author information

1
Department of Life Science Frontiers, Center for iPS Cell Research and Application (CiRA), Kyoto University, 53 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto, 606-8507, Japan. tikeda@cira.kyoto-u.ac.jp.
2
Department of Life Science Frontiers, Center for iPS Cell Research and Application (CiRA), Kyoto University, 53 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto, 606-8507, Japan.
3
RIKEN Center for Developmental Biology (CDB), 2-2-3 Minatojima-minamimachi, Chuo-ku, Kobe, 650-0047, Japan.
4
Department of Diagnostic Pathology, Kyoto University Hospital, 54 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto, 606-8507, Japan.
5
Hakubi Center for Advanced Research, Kyoto University, Yoshida-honmachi, Sakyo-ku, Kyoto, 606-8501, Japan.
6
Faculty of Biology-Oriented Science and Technology, Laboratory of Molecular Developmental Biology, Kindai University, 930 Nishimitani, Kinokawa-shi, Wakayama, 649-6493, Japan.
7
Division of Stem Cell Pathology, Center for Experimental Medicine and Systems Biology, The Institute of Medical Science, The University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo, 108-8639, Japan.
8
Institute for Integrated Cell-Material Sciences (WPI-iCeMS), Kyoto University, Kyoto, 606-8507, Japan.
9
AMED-CREST, AMED 1-7-1 Otemachi, Chiyodaku, Tokyo, 100-0004, Japan.
10
Department of Life Science Frontiers, Center for iPS Cell Research and Application (CiRA), Kyoto University, 53 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto, 606-8507, Japan. okita@cira.kyoto-u.ac.jp.
11
Department of Life Science Frontiers, Center for iPS Cell Research and Application (CiRA), Kyoto University, 53 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto, 606-8507, Japan. smasui@cira.kyoto-u.ac.jp.
12
CREST (Core Research for Evolutional Science and Technology), JST (Japan Science and Technology Agency), Honcho 4-1-8, Kawaguchi, Saitama, 332-0012, Japan. smasui@cira.kyoto-u.ac.jp.

Abstract

Multicellular organisms consist of multiple cell types. The identity of these cells is primarily maintained by cell-type-specific gene expression programs; however, mechanisms that suppress these programs are poorly defined. Here we show that serum response factor (Srf), a transcription factor that is activated by various extracellular stimuli, can repress cell-type-specific genes and promote cellular reprogramming to pluripotency. Manipulations that decrease β-actin monomer quantity result in the nuclear accumulation of Mkl1 and the activation of Srf, which downregulate cell-type-specific genes and alter the epigenetics of regulatory regions and chromatin organization. Mice overexpressing Srf exhibit various pathologies including an ulcerative colitis-like symptom and a metaplasia-like phenotype in the pancreas. Our results demonstrate an unexpected function of Srf via a mechanism by which extracellular stimuli actively destabilize cell identity and suggest Srf involvement in a wide range of diseases.

PMID:
29643333
PMCID:
PMC5895821
DOI:
10.1038/s41467-018-03748-1
[Indexed for MEDLINE]
Free PMC Article

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