期刊
GENES & DEVELOPMENT
卷 31, 期 17, 页码 1795-1808出版社
COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT
DOI: 10.1101/gad.303321.117
关键词
dynamics; enhancer; CRISPR; naive pluripotency
资金
- California Institute of Regenerative Medicine [LA1-08013]
- Janelia visitor program
- National Institute of Arthritis and Musculoskeletal and Skin Diseases of the National Institutes of Health
- Howard Hughes Medical Institute
Transcription factor (TF)-directed enhanceosome assembly constitutes a fundamental regulatory mechanism driving spatiotemporal gene expression programs during animal development. Despite decades of study, we know little about the dynamics or order of events animating TF assembly at cis-regulatory elements in living cells and the long-range molecular dialog between enhancers and promoters. Here, combining genetic, genomic, and imaging approaches, we characterize a complex long-range enhancer cluster governing Kruppel-like factor 4 (Klf4) expression in naive pluripotency. Genome editing by CRISPR/Cas9 revealed that OCT4 and SOX2 safeguard an accessible chromatin neighborhood to assist the binding of other TFs/cofactors to the enhancer. Single-molecule live-cell imaging uncovered that two naive pluripotency TFs, STAT3 and ESRRB, interrogate chromatin in a highly dynamic manner, in which SOX2 promotes ESRRB target search and chromatin-binding dynamics through a direct protein-tethering mechanism. Together, our results support a highly dynamic yet intrinsically ordered enhanceosome assembly to maintain the finely balanced transcription program underlying naive pluripotency.
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