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Heterochromatin loosening by the Oct4 linker region facilitates Klf4 binding and iPSC reprogramming
Author(s) -
Chen Keshi,
Long Qi,
Xing Guangsuo,
Wang Tianyu,
Wu Yi,
Li Linpeng,
Qi Juntao,
Zhou Yanshuang,
Ma Bochao,
Schöler Hans R,
Nie Jinfu,
Pei Duanqing,
Liu Xingguo
Publication year - 2019
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.15252/embj.201899165
Subject(s) - regenerative medicine , biomedicine , stem cell , china , reprogramming , chinese academy of sciences , stem cell biology , klf4 , induced pluripotent stem cell , library science , biology , medicine , political science , embryonic stem cell , bioinformatics , cell , microbiology and biotechnology , genetics , computer science , gene , embryo , reproductive technology , law , embryogenesis
Abstract The success of Yamanaka factor reprogramming of somatic cells into induced pluripotent stem cells suggests that some factor(s) must remodel the nuclei from a condensed state to a relaxed state. How factor‐dependent chromatin opening occurs remains unclear. Using FRAP and ATAC ‐seq, we found that Oct4 acts as a pioneer factor that loosens heterochromatin and facilitates the binding of Klf4 and the expression of epithelial genes in early reprogramming, leading to enhanced mesenchymal‐to‐epithelial transition. A mutation in the Oct4 linker, L80A, which shows impaired interaction with the BAF complex component Brg1, is inactive in heterochromatin loosening. Oct4‐L80A also blocks the binding of Klf4 and retards MET . Finally, vitamin C or Gadd45a could rescue the reprogramming deficiency of Oct4‐L80A by enhancing chromatin opening and Klf4 binding. These studies reveal a cooperation between Oct4 and Klf4 at the chromatin level that facilitates MET at the cellular level and shed light into the research of multiple factors in cell fate determination.