Heterochromatin loosening by the Oct4 linker region facilitates Klf4 binding and iPSC reprogramming.
EMBO J
; 39(1): e99165, 2020 01 02.
Article
em En
| MEDLINE
| ID: mdl-31571238
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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Texto completo:
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Base de dados:
MEDLINE
Assunto principal:
Heterocromatina
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Histonas
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Células Epiteliais
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Fatores de Transcrição Kruppel-Like
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Fator 3 de Transcrição de Octâmero
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Reprogramação Celular
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Células-Tronco Pluripotentes Induzidas
Limite:
Animals
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Humans
Idioma:
En
Ano de publicação:
2020
Tipo de documento:
Article