TY - JOUR
T1 - Phase separation of ligand-activated enhancers licenses cooperative chromosomal enhancer assembly
AU - Nair, Sreejith J.
AU - Yang, Lu
AU - Meluzzi, Dario
AU - Oh, Soohwan
AU - Yang, Feng
AU - Friedman, Meyer J.
AU - Wang, Susan
AU - Suter, Tom
AU - Alshareedah, Ibraheem
AU - Gamliel, Amir
AU - Ma, Qi
AU - Zhang, Jie
AU - Hu, Yiren
AU - Tan, Yuliang
AU - Ohgi, Kenneth A.
AU - Jayani, Ranveer Singh
AU - Banerjee, Priya R.
AU - Aggarwal, Aneel K.
AU - Rosenfeld, Michael G.
N1 - Publisher Copyright:
© 2019, The Author(s), under exclusive licence to Springer Nature America, Inc.
PY - 2019/3/1
Y1 - 2019/3/1
N2 - 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.
AB - 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.
UR - https://www.scopus.com/pages/publications/85062468185
U2 - 10.1038/s41594-019-0190-5
DO - 10.1038/s41594-019-0190-5
M3 - Article
C2 - 30833784
AN - SCOPUS:85062468185
SN - 1545-9993
VL - 26
SP - 193
EP - 203
JO - Nature Structural and Molecular Biology
JF - Nature Structural and Molecular Biology
IS - 3
ER -