Journal
NATURE COMMUNICATIONS
Volume 9, Issue -, Pages -Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/s41467-018-03748-1
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Funding
- CREST, JST
- Core Center for iPS Cell Research, Research Center Network for Realization of Regenerative Medicine from Japan Agency for Medical Research and Development, AMED
- Takeda Science Foundation
- Naito Foundation
- World Premier International Research Center Initiative (WPI)
- iPS Cell Research Fund
- Japanese Society for the Promotion of Science KAKENHI [JP26830138, JP26840076]
- World-Leading Innovative Research and Development on Science and Technology (FIRST Program) of JSPS
- Grants-in-Aid for Scientific Research [16H01222, 15H05581, 16H01321, 16H05042] Funding Source: KAKEN
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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 beta-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.
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