BET Bromodomain Inhibition Releases the Mediator Complex from Select cis-Regulatory Elements

Bhagwat, A. S., Roe, J. S., Mok, B. Y., Hohmann, A. F., Shi, J., Vakoc, C. R. (April 2016) BET Bromodomain Inhibition Releases the Mediator Complex from Select cis-Regulatory Elements. Cell Rep, 15 (3). pp. 519-30. ISSN 2211-1247 (Electronic)

URL: http://www.ncbi.nlm.nih.gov/pubmed/27068464
DOI: 10.1016/j.celrep.2016.03.054

Abstract

The bromodomain and extraterminal (BET) protein BRD4 can physically interact with the Mediator complex, but the relevance of this association to the therapeutic effects of BET inhibitors in cancer is unclear. Here, we show that BET inhibition causes a rapid release of Mediator from a subset of cis-regulatory elements in the genome of acute myeloid leukemia (AML) cells. These sites of Mediator eviction were highly correlated with transcriptional suppression of neighboring genes, which are enriched for targets of the transcription factor MYB and for functions related to leukemogenesis. A shRNA screen of Mediator in AML cells identified the MED12, MED13, MED23, and MED24 subunits as performing a similar regulatory function to BRD4 in this context, including a shared role in sustaining a block in myeloid maturation. These findings suggest that the interaction between BRD4 and Mediator has functional importance for gene-specific transcriptional activation and for AML maintenance.

Item Type: Paper
Subjects: bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types > BET bromodomain coactivator protein
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types > BET bromodomain coactivator protein > Brd4
CSHL Authors:
Communities: CSHL Cancer Center Program > Gene Regulation and Cell Proliferation
CSHL labs > Vakoc lab
Watson School > Publications
Depositing User: Matt Covey
Date: 19 April 2016
Date Deposited: 26 Apr 2016 16:33
Last Modified: 03 Jan 2019 21:06
PMCID: PMC4838499
Related URLs:
URI: http://repository.cshl.edu/id/eprint/32622

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