Journal
EMBO JOURNAL
Volume 39, Issue 1, Pages -Publisher
WILEY
DOI: 10.15252/embj.201899165
Keywords
heterochromatin loosening; Klf4; mesenchymal-to-epithelial transition; Oct4; reprogramming
Categories
Funding
- National Key Research and Development Program of China [2018YFA0107100, 2017YFA0106300, 2017YFA0102900, 2017YFC1001602, 2016YFA0100300, 2017YFA0504100]
- Strategic Priority Research Program of the Chinese Academy of Sciences [XDA16030505, XDA16010505]
- National Natural Science Foundation projects of China [U1601227, 31622037, 31631163001, 81570520, 31701281, 31701106, 31601176, 31601088, 31801168, 31900614, 31970709, 81901275, 31421004, 31530038, 31830060]
- Key Research Program of Frontier Sciences, CAS [QYZDB-SSW-SMC001, QYZDJ-SSW-SMC009]
- CAS STS Program
- Guangzhou Health Care and Cooperative Innovation Major Project [201704020218, 201604020009]
- Guangdong Province Science and Technology Program [2015TX01R047, 2017B020230005, 2017A020215056, 2017B030314056, 2018A030313825, 2018GZR110103002]
- Guangzhou Science and Technology Program from Yangtse River Scholar Bonus Schemes [201707010178, 201807010067]
- CAS Youth Innovation Promotion Association
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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.
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