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Cited by 2,595Genomics and Chromatin DynamicsRNA Research and SplicingChromatin Remodeling and Cancer

Coactivator condensation at super-enhancers links phase separation and gene control

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Sabari, Benjamin R., Dall’Agnese, Alessandra, Boija, Ann, Klein, Isaac A., Coffey, Eliot L., Shrinivas, Krishna, Abraham, Brian J., Hannett, Nancy M. +15 more·2018·Science
DOI 10.1126/science.aar3958PMC PMC6092193
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Abstract

Phase separation and gene control Many components of eukaryotic transcription machinery—such as transcription factors and cofactors including BRD4, subunits of the Mediator complex, and RNA polymerase II—contain intrinsically disordered low-complexity domains. Now a conceptual framework connecting the nature and behavior of their interactions to their functions in transcription regulation is emerging (see the Perspective by Plys and Kingston). Chong et al. found that low-complexity domains of transcription factors form concentrated hubs via functionally relevant dynamic, multivalent, and sequence-specific protein-protein interaction. These hubs have the potential to phase-separate at higher concentrations. Indeed, Sabari et al. showed that at super-enhancers, BRD4 and Mediator form liquid-like condensates that compartmentalize and concentrate the transcription apparatus to maintain expression of key cell-identity genes. Cho et al. further revealed the differential sensitivity of Mediator and RNA polymerase II condensates to selective transcription inhibitors and how their dynamic interactions might initiate transcription elongation. Science , this issue p. eaar2555 , p. eaar3958 , p. 412 ; see also p. 329

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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 [65]

  • Some established mechanisms of enhancer-gene interaction, such as high physical mobility or weak interaction networks, may not translate well to an MPRA context.

    “Also, some established mechanisms of enhancer–gene interaction, such as high physical mobility154 or weak interaction networks218, may not translate well to an MPRA context.”

    From Towards a comprehensive catalogue of validated and target-linked human enhancers (2020) · cites this paper as [218]

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Authors
Sabari, B. R., Dall’Agnese, A., Boija, A., Klein, I. A., Coffey, E. L., Shrinivas, K., Abraham, B. J., Hannett, N. M., Zamudio, A. V., Manteiga, J. C., Li, C. H., Guo, Y. E., Day, D. S., Schuijers, J., Vasile, E., Malik, S., Hnisz, D., Lee, T. I., Cisse, I. I., Roeder, R. G., Sharp, P. A., Chakraborty, A. K., & Young, R. A.
Affiliations
  • Whitehead Institute for Biomedical Research (US)
  • Harvard University (US)
  • Massachusetts Institute of Technology (US)
  • Koch Institute for Integrative Cancer Research At MIT (US)
  • Rockefeller University (US)
  • Department of Physics, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
  • Ragon Institute of MGH, MIT and Harvard (US)
Corresponding author
  • Sabari, Benjamin R.
  • Dall’Agnese, Alessandra
  • Young, Richard A.
ORCID
Venue
Science
Publisher
American Association for the Advancement of Science (AAAS)
Published
2018-07-27
Volume
361
Issue
6400
ISSN
  • 0036-8075 (ISSN-L)
  • 1095-9203
DOI
10.1126/science.aar3958
PMC
PMC6092193
OpenAlex
W2809057270
Cited by
2,595
References
11
Citations by year
2026: 319 · 2025: 362 · 2024: 316 · 2023: 334 · 2022: 327 · 2021: 392 · 2020: 281 · 2019: 211 · 2018: 49 · 2017: 1 · 2013: 1
FWCI
83.34
Type
journal article
Language
en
Open access
Locations
  • Science (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
  • CaltechAUTHORS (California Institute of Technology) (submittedVersion)
  • DSpace@MIT (Massachusetts Institute of Technology) (submittedVersion, cc-by-nc-sa)
  • MPG.PuRe (Max Planck Society) (submittedVersion, other-oa)
  • PMC
Funders
  • National Science Foundation (PHY-1743900)
  • National Institutes of Health (GM123511, P01-CA042063)
  • National Cancer Institute (P30-CA14051)
  • Hope Funds for Cancer Research
  • Damon Runyon Cancer Research Foundation (2309-17)
  • National Institute of Diabetes and Digestive and Kidney Diseases (DK071900)
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 › Chromatin Remodeling and Cancer
Keywords
super-enhancers, phase separation, liquid-like condensates, transcriptional coactivator, BRD4, Mediator complex, RNA polymerase II, low-complexity domains, intrinsically disordered regions, transcriptional regulation, cell identity genes, transcription elongation, protein-protein interaction
MeSH terms
Bromodomain Containing Proteins, Animals, Cell Nucleus, Enhancer Elements, Genetic, Gene Expression Regulation, Glycols, Humans, Nuclear Proteins, Serine, Transcription Factors, Trans-Activators, Conserved Sequence, Fluorescence Recovery After Photobleaching, NIH 3T3 Cells, Immunoprecipitation, Mice, Embryonic Stem Cells, Mediator Complex Subunit 1, Molecular Imaging, HEK293 Cells, Intrinsically Disordered Proteins

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