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Cell Rep. 2016 Apr 19;15(3):519-530. doi: 10.1016/j.celrep.2016.03.054. Epub 2016 Apr 7.

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

Author information

1
Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA; Department of Molecular Genetics and Microbiology, Stony Brook University, Stony Brook, NY 11794, USA.
2
Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA.
3
Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA; Molecular and Cellular Biology Program, Stony Brook University, Stony Brook, NY 11794, USA.
4
Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA. Electronic address: vakoc@cshl.edu.

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.

PMID:
27068464
PMCID:
PMC4838499
DOI:
10.1016/j.celrep.2016.03.054
[Indexed for MEDLINE]
Free PMC Article

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