Heterochromatin loosening by the Oct4 linker region facilitates Klf4 binding and iPSC reprogramming.,The EMBO Journal

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Heterochromatin loosening by the Oct4 linker region facilitates Klf4 binding and iPSC reprogramming.
The EMBO Journal ( IF 9.4 ) Pub Date : 2019-10-01 , DOI: 10.15252/embj.201899165
Keshi Chen _{1,

2} , Qi Long _{1,

2} , Guangsuo Xing _{1,

2,

3} , Tianyu Wang _{1,

2} , Yi Wu _{1,

2} , Linpeng Li _{1,

2} , Juntao Qi _{1,

2} , Yanshuang Zhou _{1,

2} , Bochao Ma _{1,

2} , Hans R Schöler ₄ , Jinfu Nie _{1,

2} , Duanqing Pei _{1,

2} , Xingguo Liu _{1,

2}

Affiliation

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.

中文翻译：

Oct4 连接区导致的异染色质松弛有利于 Klf4 结合和 iPSC 重编程。

山中因子将体细胞重编程为诱导多能干细胞的成功表明，某些因子必须将细胞核从凝聚态重塑为松弛态。因子依赖性染色质开放是如何发生的仍不清楚。使用 FRAP 和 ATAC-seq，我们发现 Oct4 作为一个先锋因子，可以放松异染色质并促进 Klf4 的结合和早期重编程中上皮基因的表达，从而增强间充质到上皮的转变。 Oct4 连接子 L80A 中的突变显示与 BAF 复合体成分 Brg1 的相互作用受损，在异染色质松弛中不活跃。 Oct4-L80A 还可阻断 Klf4 的结合并延迟 MET。最后，维生素 C 或 Gadd45a 可以通过增强染色质开放和 Klf4 结合来挽救 Oct4-L80A 的重编程缺陷。这些研究揭示了Oct4和Klf4在染色质水平上的合作，促进了细胞水平上的MET，并为细胞命运决定中的多种因素的研究提供了线索。

更新日期：2020-01-02

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