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

• Ikeda, Takashi

  Department of Life Science Frontiers, Center for iPS Cell Research and Application (CiRA), Kyoto University

• Hikichi, Takafusa

  Department of Life Science Frontiers, Center for iPS Cell Research and Application (CiRA), Kyoto University

• Miura, Hisashi

  RIKEN Center for Developmental Biology (CDB)

• Shibata, Hirofumi

  Department of Life Science Frontiers, Center for iPS Cell Research and Application (CiRA), Kyoto University

• Mitsunaga, Kanae

  Department of Life Science Frontiers, Center for iPS Cell Research and Application (CiRA), Kyoto University

• Yamada, Yosuke

  Department of Life Science Frontiers, Center for iPS Cell Research and Application (CiRA), Kyoto University・Department of Diagnostic Pathology, Kyoto University Hospital

• Woltjen, Knut

  Department of Life Science Frontiers, Center for iPS Cell Research and Application (CiRA), Kyoto University・Hakubi Center for Advanced Research, Kyoto University

• Miyamoto, Kei

  Faculty of Biology-Oriented Science and Technology, Laboratory of Molecular Developmental Biology, Kindai University

• Hiratani, Ichiro

  RIKEN Center for Developmental Biology (CDB)

• Yamada, Yasuhiro

  Department of Life Science Frontiers, Center for iPS Cell Research and Application (CiRA), Kyoto University・Division of Stem Cell Pathology, Center for Experimental Medicine and Systems Biology, The Institute of Medical Science, The University of Tokyo・Institute for Integrated Cell-Material Sciences (WPI-iCeMS), Kyoto University

• Hotta, Akitsu

  Department of Life Science Frontiers, Center for iPS Cell Research and Application (CiRA), Kyoto University・Institute for Integrated Cell-Material Sciences (WPI-iCeMS), Kyoto University

• Yamamoto, Takuya

  Department of Life Science Frontiers, Center for iPS Cell Research and Application (CiRA), Kyoto University・Institute for Integrated Cell-Material Sciences (WPI-iCeMS), Kyoto University・AMED-CREST

• Okita, Keisuke

  Department of Life Science Frontiers, Center for iPS Cell Research and Application (CiRA), Kyoto University

• Masui, Shinji

  Department of Life Science Frontiers, Center for iPS Cell Research and Application (CiRA), Kyoto University・CREST (Core Research for Evolutional Science and Technology), JST (Japan Science and Technology Agency)

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.

Journal

• Nature Communications

  Nature Communications 9 1387-, 2018-04-11

  Springer Nature

Keywords

• General Physics and Astronomy
• General Biochemistry, Genetics and Molecular Biology
• General Chemistry
• Multidisciplinary

Details

• CRID: 1050845763137791616
• NII Article ID: 120006517799
• ISSN: 20411723
• DOI: 10.1038/s41467-018-03748-1
• HANDLE: 2433/234240
• Web Site: https://www.nature.com/articles/s41467-018-03748-1.pdf
• Web Site: https://www.nature.com/articles/s41467-018-03748-1
• Text Lang: en
• Article Type: journal article
• Data Source:
  • IRDB
  • Crossref
  • CiNii Articles
  • KAKEN