Source: Zhongshan School of Medicine
Edited by: Tan Rongyu, Wang Dongmei

The eukaryotic three-dimensional (3D) genome is organized in a hierarchical order, mainly comprising compartments, topological-associated domains (TADs), and chromatin loops from large to small scales. 3D chromatin architectures are drastically altered during cell fate transitions, which plays an important role to promote cell fate transitions. TADs are usually considered to be stable among different cell types and species. However, recent studies have reported the loss of TADs during pluripotent stem cell (PSC) differentiation, indicating that they are likely to reorganize in these biological processes. Therefore, it is significant to clarify the relationship between TAD reorganization and cell fate transitions.

On 25 May 2021, the work of Professor Ding Junjun’s team entitled “Phase separation of OCT4 controls TAD reorganization to promote cell fate transitions” is published in Cell Stem Cell, which for the first time illuminates that phase separation promotes cell fate transitions via regulating higher-order chromatin 3D architectures.


In this study, 3D genome, proteome, transcriptome and epigenome were integrated to map the dynamics of chromatin 3D architectures during somatic cell reprogramming. TAD reorganization was observed, which contributes largely to cell fate transitions. Moreover, the dynamics of OCT4-mediated chromatin loops promote TAD reorganization by regulating the binding of CTCF on TAD boundaries. Further, OCT4 phase-separated condensates which concentrate chromatin loops regulate TAD reorganization. Interestingly, manipulation of TAD reorganization or OCT4 phase separation can influence cell fate transitions. Finally, TAD reorganization-based new algorithm was developed to identify novel cell fate regulators, which were validated by functional study.

It is the first work to establish the regulatory network among phase separation, higher-order chromatin structures and cell fate transitions. New methods were set up to control cell fate transitions by manipulating TAD structures or phase separation. New algorithm was developed to precisely predict novel cell fate regulators.

Wang Jia, research fellow of Zhongshan School of Medicine, is the first author of the paper, Yu Haopeng and Ma Qian are co-first authors, Ding Junjun, Professor of Zhongshan School of Medicine at Sun Yat-sen University, is the only corresponding author.

Link to the paper: https://www.cell.com/cell-stem-cell/fulltext/S1934-5909(21)00181-8