Phase separation of ligand-activated enhancers licenses cooperative chromosomal enhancer assembly

Sreejith J. Nair, Lu Yang, Dario Meluzzi, Soohwan Oh, Feng Yang, Meyer J. Friedman, Susan Wang, Tom Suter, Ibraheem Alshareedah, Amir Gamliel, Qi Ma, Jie Zhang, Yiren Hu, Yuliang Tan, Kenneth A. Ohgi, Ranveer Singh Jayani, Priya R. Banerjee, Aneel K. Aggarwal, Michael G. Rosenfeld

Research output: Contribution to journalArticlepeer-review

149 Scopus citations

Abstract

A crucial feature of differentiated cells is the rapid activation of enhancer-driven transcriptional programs in response to signals. The potential contributions of physicochemical properties of enhancer assembly in signaling events remain poorly understood. Here we report that in human breast cancer cells, the acute 17β-estradiol-dependent activation of functional enhancers requires assembly of an enhancer RNA–dependent ribonucleoprotein (eRNP) complex exhibiting properties of phase-separated condensates. Unexpectedly, while acute ligand-dependent assembly of eRNPs resulted in enhancer activation sensitive to chemical disruption of phase separation, chronically activated enhancers proved resistant to such disruption, with progressive maturation of eRNPs to a more gel-like state. Acute, but not chronic, stimulation resulted in ligand-induced, condensin-dependent changes in spatial chromatin conformation based on homotypic enhancer association, resulting in cooperative enhancer-activation events. Thus, distinct physicochemical properties of eRNP condensates on enhancers serve as determinants of rapid ligand-dependent alterations in chromosomal architecture and cooperative enhancer activation.

Original languageEnglish
Pages (from-to)193-203
Number of pages11
JournalNature Structural and Molecular Biology
Volume26
Issue number3
DOIs
StatePublished - 1 Mar 2019

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