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A dynamic interplay of enhancer elements regulates Klf4 expression in naïve pluripotency

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 el...

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Detalles Bibliográficos
Autores principales: Xie, Liangqi, Torigoe, Sharon E., Xiao, Jifang, Mai, Daniel H., Li, Li, Davis, Fred P., Dong, Peng, Marie-Nelly, Herve, Grimm, Jonathan, Lavis, Luke, Darzacq, Xavier, Cattoglio, Claudia, Liu, Zhe, Tjian, Robert
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Cold Spring Harbor Laboratory Press 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5666677/
https://www.ncbi.nlm.nih.gov/pubmed/28982762
http://dx.doi.org/10.1101/gad.303321.117
Descripción
Sumario: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 Krüppel-like factor 4 (Klf4) expression in naïve 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 naïve 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 naïve pluripotency.