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

Publication date: Available online 7 April 2016
Source:Cell Reports
Author(s): Anand S. Bhagwat, Jae-Seok Roe, Beverly Y.L. Mok, Anja F. Hohmann, Junwei Shi, Christopher R. Vakoc
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.

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Teaser

In this study, Bhagwat et al. show that the Mediator complex and BRD4 are linked coactivators that support gene-specific transcriptional activation in leukemia cells. They provide evidence that small-molecule inhibitors of BRD4 exert anti-leukemia effects by interfering with Mediator function to suppress transcription.


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