Phase separation of OCT4 controls TAD reorganization to promote cell fate transitions
Phase separation of OCT4 controls TAD reorganization to promote cell fate transitions
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OCT4 的相分离控制 TAD 重组以促进细胞命运转变
DOI：
10.1016/j.stem.2021.04.023
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发表时间：
2021-10-07
期刊：
影响因子：
23.9
通讯作者：
Ding, Junjun
中科院分区：
文献类型：
--
作者：
Wang, Jia;Yu, Haopeng;Ding, Junjun
拓扑相关结构域（TADs）被认为是相对稳定的跨细胞类型，虽然一些重组已被观察到在细胞分化。然而，很少有人知道的机制，通过它的转录重组影响细胞的命运或主转录因子如何影响细胞命运转换过程中的转录结构。在这里，我们展示了体细胞重编程过程中广泛的重组，这与基因转录和细胞特性的变化相关。操纵DNA重组促进重编程，并且OCT 4相分离的浓缩物中浓缩的染色质环的动力学有助于DNA重组。破坏OCT4相分离会减弱DNA重组和重编程，这可以通过将固有无序区（IDR）融合到OCT4来挽救。我们开发了一种名为基于重组的多组学分析（MPEGMAN）的方法，该方法确定了重编程调节因子。总之，这些发现阐明了在细胞重编程中由OCT 4相分离调节的细胞重组的作用和机制。
Topological-associated domains (TADs) are thought to be relatively stable across cell types, although some TAD reorganization has been observed during cellular differentiation. However, little is known about the mechanisms through which TAD reorganization affects cell fate or how master transcription factors affect TAD structures during cell fate transitions. Here, we show extensive TAD reorganization during somatic cell reprogramming, which is correlated with gene transcription and changes in cellular identity. Manipulating TAD reorganization promotes reprogramming, and the dynamics of concentrated chromatin loops in OCT4 phase separated condensates contribute to TAD reorganization. Disrupting OCT4 phase separation attenuates TAD reorganization and reprogramming, which can be rescued by fusing an intrinsically disordered region (IDR) to OCT4. We developed an approach termed TAD reorganization-based multiomics analysis (TAD MAN), which identified reprogramming regulators. Together, these findings elucidate a role and mechanism of TAD reorganization, regulated by OCT4 phase separation, in cellular reprogramming.