Mediator Condensates Localize Signaling Factors to Key Cell Identity Genes

Mol Cell. 2019 Dec 5;76(5):753-766.e6. doi: 10.1016/j.molcel.2019.08.016. Epub 2019 Sep 25.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line
  • Enhancer Elements, Genetic / genetics*
  • Gene Expression Regulation / physiology
  • Humans
  • Intrinsically Disordered Proteins / metabolism
  • Mediator Complex / metabolism*
  • Mediator Complex / physiology
  • STAT Transcription Factors / metabolism
  • STAT3 Transcription Factor / metabolism
  • Signal Transduction / physiology
  • Smad3 Protein / metabolism
  • TGF-beta Superfamily Proteins / metabolism
  • Transcription Factors / metabolism*
  • Transcription, Genetic
  • Wnt Signaling Pathway
  • beta Catenin / metabolism


  • Intrinsically Disordered Proteins
  • Mediator Complex
  • STAT Transcription Factors
  • STAT3 Transcription Factor
  • Smad3 Protein
  • TGF-beta Superfamily Proteins
  • Transcription Factors
  • beta Catenin