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Cited by 1,815Genomics and Chromatin DynamicsRNA Research and SplicingGene Regulatory Network Analysis

Transcription Factors Activate Genes through the Phase-Separation Capacity of Their Activation Domains

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Boija, Ann, Klein, Isaac A., Sabari, Benjamin R., Dall’Agnese, Alessandra, Coffey, Eliot L., Zamudio, Alicia V., Li, Charles H., Shrinivas, Krishna +11 more·2018·Cell
DOI 10.1016/j.cell.2018.10.042PMC PMC6295254
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Abstract

Gene expression is controlled by transcription factors (TFs) that consist of DNA-binding domains (DBDs) and activation domains (ADs). The DBDs have been well characterized, but little is known about the mechanisms by which ADs effect gene activation. Here, we report that diverse ADs form phase-separated condensates with the Mediator coactivator. For the OCT4 and GCN4 TFs, we show that the ability to form phase-separated droplets with Mediator in vitro and the ability to activate genes in vivo are dependent on the same amino acid residues. For the estrogen receptor (ER), a ligand-dependent activator, we show that estrogen enhances phase separation with Mediator, again linking phase separation with gene activation. These results suggest that diverse TFs can interact with Mediator through the phase-separating capacity of their ADs and that formation of condensates with Mediator is involved in gene activation.

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  • Current theories propose liquid-liquid phase separation and some form of transcription factor trapping or engagement of transcription factors in multivalent interactions independent of assembly into phase-separated liquid-like droplets.

    “current theories propose liquid-liquid phase separation18,64–66 and some form of TF trapping22,67 or engagement of TFs in multivalent interactions independent of assembly into phase-separated liquid-like droplets.68”

    From Super-enhancers include classical enhancers and facilitators to fully activate gene expression (2023) · cites this paper as [64]

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Authors
Boija, A., Klein, I. A., Sabari, B. R., Dall’Agnese, A., Coffey, E. L., Zamudio, A. V., Li, C. H., Shrinivas, K., Manteiga, J. C., Hannett, N. M., Abraham, B. J., Afeyan, L. K., Guo, Y. E., Rimel, J. K., Fant, C. B., Schuijers, J., Lee, T. I., Taatjes, D. J., & Young, R. A.
Affiliations
  • Whitehead Institute for Biomedical Research (US)
  • Harvard University (US)
  • Massachusetts Institute of Technology (US)
  • University of Colorado Boulder (US)
Corresponding author
Young, Richard A.
ORCID
Venue
Cell
Publisher
Elsevier BV
Published
2018-12
Volume
175
Issue
7
Pages
1842-1855.e16
ISSN
0092-8674 (ISSN-L)
DOI
10.1016/j.cell.2018.10.042
PMC
PMC6295254
OpenAlex
W2901209536
Cited by
1,815
References
2
Citations by year
2026: 190 · 2025: 253 · 2024: 264 · 2023: 258 · 2022: 241 · 2021: 291 · 2020: 191 · 2019: 119 · 2018: 6
FWCI
54.43
Type
journal article
Language
en
Open access
Licence
Locations
  • Cell (publishedVersion, other-oa)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
  • DSpace@MIT (Massachusetts Institute of Technology) (submittedVersion, cc-by-nc-nd)
  • PMC
Funders
  • NIH (GM123511, T32GM08759)
  • NSF (PHY1743900)
  • Swedish Research Council Postdoctoral Fellowship (VR 2017-00372, T32CA009172)
  • Damon Runyon Cancer Research Foundation Fellowship (2309-17)
  • Hope Funds for Cancer Research fellowship
  • Cancer Research Institute Irvington Fellowship
  • NWO Rubicon Fellowship
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Research and Splicing
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gene Regulatory Network Analysis
Keywords
transcription factors, transactivation domain, phase separation, biomolecular condensates, gene activation, Oct4, GCN4, estrogen receptor, ligand-dependent activation, DNA-binding domain
MeSH terms
Mouse Embryonic Stem Cells, Protein Domains, Animals, Humans, Receptors, Estrogen, Transcriptional Activation, Octamer Transcription Factor-3, Mice, HEK293 Cells

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