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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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