CaltechAUTHORS
Published December 5, 2019 | Version Accepted Version + Supplemental Material
Journal Article Open

Mediator Condensates Localize Signaling Factors to Key Cell Identity Genes

Creators

  • 1. ROR icon Whitehead Institute for Biomedical Research
  • 2. ROR icon Massachusetts Institute of Technology
  • 3. ROR icon Harvard University
  • 4. ROR icon Dana-Farber Cancer Institute
  • 5. ROR icon University of Colorado Boulder
  • 6. ROR icon St. Jude Children's Research Hospital

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.

Additional Information

© 2019 Elsevier. Received 14 February 2019, Revised 14 June 2019, Accepted 16 August 2019, Available online 25 September 2019. 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' 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.). Author Contributions. 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. Data and Code Availability. All software and code generated in this project are publicly available at: https://github.com/jehenninger/FISH_IF and https://github.com/jehenninger/in_vitro_droplet_assay ChIP-seq data were deposited into GEO under the accession number GEO: GSE134387. Raw images associated with presented figures have been deposited in the Mendeley databases: https://doi.org/10.17632/x4j73x87bj.1 https://doi.org/10.17632/99bt56v4zs.1 Declaration of Interests. 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.

Attached Files

Accepted Version - nihms-1538552.pdf

Supplemental Material - 1-s2.0-S1097276519306550-mmc1.pdf

Supplemental Material - 1-s2.0-S1097276519306550-mmc2.mp4

Supplemental Material - 1-s2.0-S1097276519306550-mmc3.mp4

Supplemental Material - 1-s2.0-S1097276519306550-mmc4.mp4

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Additional details

Identifiers

PMCID
PMC6898777
Eprint ID
106660
Resolver ID
CaltechAUTHORS:20201112-143949613

Related works

Describes
https://github.com/jehenninger/FISH_IF (URL)
https://github.com/jehenninger/in_vitro_droplet_assay (URL)
http://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE134387 (URL)
10.17632/x4j73x87bj.1 (DOI)
10.17632/99bt56v4zs.1 (DOI)

Funding

NIH
GM123511
NSF
PHY-1743900
NIH
GM117370
NSF Graduate Research Fellowship
NIH Predoctoral Fellowship
T32CA009172
NIH
DP2CA195769
NIH
GM134734
Pew Charitable Trust
Deutsche Forschungsgemeinschaft (DFG)
DE 3069/1-1
Swedish Research Council
VR 2017-00372
Novo Nordisk

Dates

Created
2020-11-16
Created from EPrint's datestamp field
Updated
2023-06-01
Created from EPrint's last_modified field