Mediator Condensates Localize Signaling Factors to Key Cell Identity Genes

Alicia V. Zamudio, Alessandra Dall'Agnese, Jonathan E. Henninger, John C. Manteiga, Lena K. Afeyan, Nancy M. Hannett, Eliot L. Coffey, Charles H. Li, Ozgur Oksuz, Benjamin R. Sabari, Ann Boija, Isaac A. Klein, Susana W. Hawken, Jan Hendrik Spille, Tim Michael Decker, Ibrahim I. Cisse, Brian J. Abraham, Tong I. Lee, Dylan J. Taatjes, Jurian Schuijers*Richard A. Young*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

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.

Original languageEnglish
Pages (from-to)753-766.e6
JournalMolecular Cell
Volume76
Issue number5
DOIs
Publication statusPublished - 5 Dec 2019
Externally publishedYes

Keywords

  • gene regulation
  • JAK/STAT
  • signaling pathway
  • TGF-β
  • transcriptional condensates
  • WNT

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