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Heterochromatin loosening by the Oct4 linker region facilitates Klf4 binding and iPSC reprogramming

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·2020·The EMBO Journal
DOI 10.15252/embj.201899165
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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.

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  • During full reprogramming, OCT4 directly recruits the BAF chromatin remodeling complex to promote a euchromatic chromatin state that enhances reprogramming factor binding.

    “First, OCT4 directly recruits the BAF chromatin remodeling complex to promote a euchromatic chromatin state that enhances reprogramming factor binding [37][38][39] .”

    From Mechanisms, pathways and strategies for rejuvenation through epigenetic reprogramming (2023) · cites this paper as [37]

  • OSKM facilitates MET by suppressing the regulation of epithelial-to-mesenchymal transition through multiple mechanisms, such as OCT4 and MYC repression of TGFβ signaling, OCT4 and SOX2 activation of miR-200 family, and OCT4 and KLF4 chromatin opening and activation of epithelial genes.

    “Interestingly, OSKM facilitates MET by suppressing the regulation of epithelial-to-mesenchymal transition through multiple mechanisms, such as OCT4 and MYC repression of TGFβ signaling 33,94 , OCT4 and SOX2 activation of miR-200 family 33,98 , and OCT4 and KLF4 chromatin opening and activation of epithelial genes 37 .”

    From Mechanisms, pathways and strategies for rejuvenation through epigenetic reprogramming (2023) · cites this paper as [37]

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Metadata

Authors
Chen, K., Long, Q., Xing, G., Wang, T., Wu, Y., Li, L., Qi, J., Zhou, Y., Ma, B., Schöler, H. R., Nie, J., Pei, D., & Liu, X.
Venue
The EMBO Journal
Publisher
Springer Science and Business Media LLC
Published
2019-10-01
Volume
39
Issue
1
ISSN
  • 0261-4189
  • 1460-2075
DOI
10.15252/embj.201899165
Cited by
40
References
8
Language
en
Licence
Funders
  • the National Key Research and Development Program of China (2018YFA0107100, 2017YFA0106300, 2017YFA0102900, 2017YFC1001602, 2016YFA0100300, 2017YFA0504100)
  • the Strategic Priorty Research Program of the Chinese Academy of Sciences (XDA16030505, XDA16010505)
  • the National Natural Science Foundation projects of China (U1601227, 31622037, 31631163001, 81570520, 31801168, 31701281, 31701106, 31601176, 31601088, 31900614, 31970709, 81901275, 31421004, 31530038, 31830060)
  • the Key Research Program of Frontier Sciences, CAS (QYZDB‐SSW‐SMC001, QYZDJ‐SSW‐SMC009)
  • 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 (201707010178, 201807010067)
  • Grant from Yangtse River Scholar Bonus Schemes
  • CAS Youth Innovation Promotion Association
  • CAS STS Program

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