@article{b8b77eb212d04fabab51bebcbe0f5d1b,
title = "Mediator Condensates Localize Signaling Factors to Key Cell Identity Genes",
abstract = "The gene expression programs that define the identity of each cell are controlled by master transcription factors (TFs) that bind cell-type-specific enhancers, as well as signaling factors, which bring extracellular stimuli to these enhancers. Recent studies have revealed that master TFs form phase-separated condensates with the Mediator coactivator at super-enhancers. Here, we present evidence that signaling factors for the WNT, TGF-β, and JAK/STAT pathways use their intrinsically disordered regions (IDRs) to enter and concentrate in Mediator condensates at super-enhancers. We show that the WNT coactivator β-catenin interacts both with components of condensates and DNA-binding factors to selectively occupy super-enhancer-associated genes. We propose that the cell-type specificity of the response to signaling is mediated in part by the IDRs of the signaling factors, which cause these factors to partition into condensates established by the master TFs and Mediator at genes with prominent roles in cell identity.",
keywords = "JAK/STAT, TGF-β, WNT, gene regulation, signaling pathway, transcriptional condensates",
author = "Zamudio, {Alicia V.} and Alessandra Dall'Agnese and Henninger, {Jonathan E.} and Manteiga, {John C.} and Afeyan, {Lena K.} and Hannett, {Nancy M.} and Coffey, {Eliot L.} and Li, {Charles H.} and Ozgur Oksuz and Sabari, {Benjamin R.} and Ann Boija and Klein, {Isaac A.} and Hawken, {Susana W.} and Spille, {Jan Hendrik} and Decker, {Tim Michael} and Cisse, {Ibrahim I.} and Abraham, {Brian J.} and Lee, {Tong I.} and Taatjes, {Dylan J.} and Jurian Schuijers and Young, {Richard A.}",
note = "Funding Information: We thank the Whitehead Institute Genome Technology Core, FACS facility, Keck Imaging Facility, and Harvard Center for Biological Imaging for their assistance. We thank Krishna Shrinivas for help with the quantification of the FRAP data. This work is supported by NIH grant GM123511 (to R.A.Y.), National Science Foundation (NSF) grant PHY1743900 (to R.A.Y.), funds from Novo Nordisk (to R.A.Y.), NIH grant GM117370 (to D.J.T.), an NSF Graduate Research Fellowship (to A.V.Z.), NIH grant T32CA009172 (to I.A.K.), NIH Director's New Innovator award DP2CA195769 (to I.I.C.), NIH grant GM134734 (to I.I.C.), Pew Charitable Trusts{\textquoteright} Pew Biomedical Scholars Program grant (to I.I.C.), Deutsch Forschungsgemeinschaft (DFG) Research Fellowship DE 3069/1-1 (to T.-M.D.), and Swedish Research Council Postdoctoral Fellowship VR 2017-00372 (to A.B.). Conceptualization, J.S. A.V.Z. and R.A.Y.; Methodology, J.S. and A.V.Z.; Software & Formal Analysis, J.S. A.V.Z. C.H.L. and J.E.H.; Investigation, J.S. A.V.Z. A.D. J.H. J.C.M. N.M.H. L.K.A. E.L.C. A.B. B.R.S. S.W.H. J.-H.S. I.I.C. T.-M.D. and D.J.T.; Writing, J.S. A.V.Z. T.I.L. and R.A.Y.; Visualization, J.S. and A.V.Z.; Supervision, J.S. and R.A.Y.; Funding Acquisition, R.A.Y. The Whitehead Institute plans to file a patent application based in part on this paper. R.A.Y. is a founder and shareholder of Syros Pharmaceuticals, Camp4 Therapeutics, Omega Therapeutics, and Dewpoint Therapeutics. B.J.A. and T.I.L. are shareholders of Syros Pharmaceuticals. T.I.L. is a consultant to Camp4 Therapeutics. Funding Information: We thank the Whitehead Institute Genome Technology Core, FACS facility, Keck Imaging Facility, and Harvard Center for Biological Imaging for their assistance. We thank Krishna Shrinivas for help with the quantification of the FRAP data. This work is supported by NIH grant GM123511 (to R.A.Y.), National Science Foundation (NSF) grant PHY1743900 (to R.A.Y.), funds from Novo Nordisk (to R.A.Y.), NIH grant GM117370 (to D.J.T.), an NSF Graduate Research Fellowship (to A.V.Z.), NIH grant T32CA009172 (to I.A.K.), NIH Director{\textquoteright}s New Innovator award DP2CA195769 (to I.I.C.), NIH grant GM134734 (to I.I.C.), Pew Charitable Trusts {\textquoteright} Pew Biomedical Scholars Program grant (to I.I.C.), Deutsch Forschungsgemeinschaft (DFG) Research Fellowship DE 3069/1-1 (to T.-M.D.), and Swedish Research Council Postdoctoral Fellowship VR 2017-00372 (to A.B.). Publisher Copyright: {\textcopyright} 2019 Elsevier Inc.",
year = "2019",
month = dec,
day = "5",
doi = "10.1016/j.molcel.2019.08.016",
language = "English (US)",
volume = "76",
pages = "753--766.e6",
journal = "Molecular Cell",
issn = "1097-2765",
publisher = "Cell Press",
number = "5",
}