Phase separation of OCT4 controls TAD reorganization to promote cell fate transitions

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. [Display omitted] •TADs are reorganized during somatic cell reprogramming•Manipulation of TAD reorganization promotes reprogramming•OCT4 phase separation regulates TAD reorganization•Reprogramming regulators are identified by a TAD-reorganization-based algorithm, TADMAN Wang et al. provide evidence that TAD reorganization contributes to cell fate transition, and Oct4 phase separation regulates TAD reorganization. This provides insights into how a master transcription factor regulates 3D genome topology, especially TAD structures, for cell fate control.