Heterochromatin loosening by the Oct4 linker region facilitates Klf4 binding and iPSC reprogramming
Heterochromatin loosening by the Oct4 linker region facilitates Klf4 binding and iPSC reprogramming
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Oct4 连接区导致的异染色质松弛促进 Klf4 结合和 iPSC 重编程
DOI：
10.15252/embj.201899165
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发表时间：
2019-10-01
期刊：
影响因子：
11.4
通讯作者：
Liu, Xingguo
中科院分区：
文献类型：
--
作者：
Chen, Keshi;Long, Qi;Liu, Xingguo
山中因子将体细胞重新编程为诱导的多能干细胞的成功表明，必须有某种因子(S)将细胞核从凝聚状态重塑为松弛状态。依赖于因子的染色质开放是如何发生的仍不清楚。利用FRAP和ATAC-SEQ，我们发现Oct4是一个先驱因子，它松弛了异染色质，促进了KLF4的结合，促进了早期重编程中上皮基因的表达，从而促进了间充质向上皮的转化。Oct4连接子L80A的突变显示与BAF复合体成分BRG1的相互作用受损，在异染色质松动中不活跃。Oct4-L80A还阻断KLF4和阻滞剂MET的结合。维生素C或Gadd45a可通过促进染色质开放和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，并为细胞命运决定的多种因素的研究提供了线索。
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.