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 (TADMAN), which identified reprogramming regulators. Together, these findings elucidate a role and mechanism of TAD reorganization, regulated by OCT4 phase separation, in cellular reprogramming.

尽管在细胞分化过程中观察到一些 TAD 重组，但拓扑相关域 (TAD) 被认为在细胞类型中相对稳定。然而，关于 TAD 重组影响细胞命运的机制或主转录因子如何在细胞命运转变过程中影响 TAD 结构的机制知之甚少。在这里，我们展示了体细胞重编程过程中广泛的 TAD 重组，这与基因转录和细胞身份的变化相关。操纵 TAD 重组促进重编程，OCT4 相分离凝聚物中浓缩染色质环的动力学有助于 TAD 重组。破坏 OCT4 相分离会减弱 TAD 重组和重编程，这可以通过将内在无序区域 (IDR) 与 OCT4 融合来挽救。我们开发了一种称为基于 TAD 重组的多组学分析 (TADMAN) 的方法，该方法确定了重编程调节因子。总之，这些发现阐明了由 OCT4 相分离调节的 TAD 重组在细胞重编程中的作用和机制。