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Mol Cell. 2019 Sep 19. pii: S1097-2765(19)30655-0. doi: 10.1016/j.molcel.2019.08.016. [Epub ahead of print]

Mediator Condensates Localize Signaling Factors to Key Cell Identity Genes.

Author information

1
Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA; Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
2
Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA.
3
Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA; Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA.
4
Program in Computational and Systems Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
5
Department of Physics, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
6
Department of Biochemistry, University of Colorado, Boulder, Boulder, CO 80303, USA.
7
Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA; St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
8
Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA. Electronic address: j.schuijers@umcutrecht.nl.
9
Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA; Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA. Electronic address: young@wi.mit.edu.

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

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