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

Benjamin R Sabari; Alessandra Dall'Agnese; Ann Boija; Isaac A Klein; Eliot L Coffey; Krishna Shrinivas; Brian J Abraham; Nancy M Hannett; Alicia V Zamudio; John C Manteiga; Charles H Li; Yang E Guo; Daniel S Day; Jurian Schuijers; Eliza Vasile; Sohail Malik; Denes Hnisz; Tong Ihn Lee; Ibrahim I Cisse; Robert G Roeder; Phillip A Sharp; Arup K Chakraborty; Richard A Young

doi:10.1126/science.aar3958

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

Science. 2018 Jul 27;361(6400):eaar3958. doi: 10.1126/science.aar3958. Epub 2018 Jun 21.

Authors

Benjamin R Sabari¹, Alessandra Dall'Agnese¹, Ann Boija¹, Isaac A Klein^{1

2}, Eliot L Coffey^{1

3}, Krishna Shrinivas^{4

5}, Brian J Abraham¹, Nancy M Hannett¹, Alicia V Zamudio^{1

3}, John C Manteiga^{1

3}, Charles H Li^{1

3}, Yang E Guo¹, Daniel S Day¹, Jurian Schuijers¹, Eliza Vasile⁶, Sohail Malik⁷, Denes Hnisz¹, Tong Ihn Lee¹, Ibrahim I Cisse⁸, Robert G Roeder⁷, Phillip A Sharp^{3

6}, Arup K Chakraborty^{4

5

8

9

10

11}, Richard A Young^{12

3}

Affiliations

¹ Whitehead Institute for Biomedical Research, 455 Main Street, Cambridge, MA 02142, USA.
² Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA.
³ Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
⁴ Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
⁵ Institute for Medical Engineering & Science, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
⁶ Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
⁷ Laboratory of Biochemistry and Molecular Biology, The Rockefeller University, New York, NY 10065, USA.
⁸ Department of Physics, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
⁹ Department of Chemistry, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
¹⁰ Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
¹¹ Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology and Harvard, Cambridge, MA 02139, USA.
¹² Whitehead Institute for Biomedical Research, 455 Main Street, Cambridge, MA 02142, USA. young@wi.mit.edu.

Abstract

Super-enhancers (SEs) are clusters of enhancers that cooperatively assemble a high density of the transcriptional apparatus to drive robust expression of genes with prominent roles in cell identity. Here we demonstrate that the SE-enriched transcriptional coactivators BRD4 and MED1 form nuclear puncta at SEs that exhibit properties of liquid-like condensates and are disrupted by chemicals that perturb condensates. The intrinsically disordered regions (IDRs) of BRD4 and MED1 can form phase-separated droplets, and MED1-IDR droplets can compartmentalize and concentrate the transcription apparatus from nuclear extracts. These results support the idea that coactivators form phase-separated condensates at SEs that compartmentalize and concentrate the transcription apparatus, suggest a role for coactivator IDRs in this process, and offer insights into mechanisms involved in the control of key cell-identity genes.

Publication types

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

MeSH terms

Animals
Cell Nucleus / drug effects
Cell Nucleus / metabolism
Conserved Sequence
Embryonic Stem Cells / metabolism
Enhancer Elements, Genetic* / drug effects
Fluorescence Recovery After Photobleaching
Gene Expression Regulation* / drug effects
Glycols / pharmacology
HEK293 Cells
Humans
Immunoprecipitation
Intrinsically Disordered Proteins / chemistry
Intrinsically Disordered Proteins / genetics
Intrinsically Disordered Proteins / metabolism*
Mediator Complex Subunit 1 / chemistry
Mediator Complex Subunit 1 / genetics
Mediator Complex Subunit 1 / metabolism*
Mice
Molecular Imaging
NIH 3T3 Cells
Nuclear Proteins / chemistry
Nuclear Proteins / genetics
Nuclear Proteins / metabolism*
Serine / chemistry
Serine / genetics
Trans-Activators / chemistry
Trans-Activators / genetics
Trans-Activators / metabolism*
Transcription Factors / chemistry
Transcription Factors / genetics
Transcription Factors / metabolism*

Substances

Brd4 protein, mouse
Glycols
Intrinsically Disordered Proteins
Med1 protein, mouse
Mediator Complex Subunit 1
Nuclear Proteins
Trans-Activators
Transcription Factors
Serine
hexamethylene glycol

Abstract

Publication types

MeSH terms

Substances

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