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 SchuijersRichard A. Young

Research output: Contribution to journalArticle

7 Scopus citations

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 (US)
Pages (from-to)753-766.e6
JournalMolecular cell
Volume76
Issue number5
DOIs
StatePublished - Dec 5 2019
Externally publishedYes

Keywords

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

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

Fingerprint Dive into the research topics of 'Mediator Condensates Localize Signaling Factors to Key Cell Identity Genes'. Together they form a unique fingerprint.

  • Cite this

    Zamudio, A. V., Dall'Agnese, A., Henninger, J. E., Manteiga, J. C., Afeyan, L. K., Hannett, N. M., Coffey, E. L., Li, C. H., Oksuz, O., Sabari, B. R., Boija, A., Klein, I. A., Hawken, S. W., Spille, J. H., Decker, T. M., Cisse, I. I., Abraham, B. J., Lee, T. I., Taatjes, D. J., ... Young, R. A. (2019). Mediator Condensates Localize Signaling Factors to Key Cell Identity Genes. Molecular cell, 76(5), 753-766.e6. https://doi.org/10.1016/j.molcel.2019.08.016