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Nat Commun. 2019 Apr 12;10(1):1695. doi: 10.1038/s41467-019-09636-6.

MKL1-actin pathway restricts chromatin accessibility and prevents mature pluripotency activation.

Author information

1
Department of Cell Biology, Yale University, New Haven, CT, 06520, USA.
2
Yale Stem Cell Center, Yale University, New Haven, CT, 06520, USA.
3
Department of Pathology, Yale Cancer Center, Yale University, New Haven, CT, 06520, USA.
4
Department of Pediatrics, Yale University, New Haven, CT, 06520, USA.
5
Department of Medicine (Cardiology), Yale University, New Haven, CT, 06520, USA.
6
Department of Genetics, Yale University, New Haven, CT, 06520, USA.
7
Department of Laboratory Medicine, Yale University, New Haven, CT, 06520, USA.
8
Department of Cell Biology, Yale University, New Haven, CT, 06520, USA. shangqin.guo@yale.edu.
9
Yale Stem Cell Center, Yale University, New Haven, CT, 06520, USA. shangqin.guo@yale.edu.

Abstract

Actin cytoskeleton is well-known for providing structural/mechanical support, but whether and how it regulates chromatin and cell fate reprogramming is far less clear. Here, we report that MKL1, the key transcriptional co-activator of many actin cytoskeletal genes, regulates genomic accessibility and cell fate reprogramming. The MKL1-actin pathway weakens during somatic cell reprogramming by pluripotency transcription factors. Cells that reprogram efficiently display low endogenous MKL1 and inhibition of actin polymerization promotes mature pluripotency activation. Sustained MKL1 expression at a level seen in typical fibroblasts yields excessive actin cytoskeleton, decreases nuclear volume and reduces global chromatin accessibility, stalling cells on their trajectory toward mature pluripotency. In addition, the MKL1-actin imposed block of pluripotency can be bypassed, at least partially, when the Sun2-containing linker of the nucleoskeleton and cytoskeleton (LINC) complex is inhibited. Thus, we unveil a previously unappreciated aspect of control on chromatin and cell fate reprogramming exerted by the MKL1-actin pathway.

PMID:
30979898
PMCID:
PMC6461646
DOI:
10.1038/s41467-019-09636-6
[Indexed for MEDLINE]
Free PMC Article

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