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

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

Author information

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.

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PMID:
29930091
PMCID:
PMC6092193
DOI:
10.1126/science.aar3958
[Indexed for MEDLINE]
Free PMC Article

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