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

Anand S. Bhagwat; Jae Seok Roe; Beverly Y.L. Mok; Anja F. Hohmann; Junwei Shi; Christopher R. Vakoc

doi:10.1016/j.celrep.2016.03.054

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

Anand S. Bhagwat, Jae Seok Roe, Beverly Y.L. Mok, Anja F. Hohmann, Junwei Shi, Christopher R. Vakoc

Department of Biochemistry

Research output: Contribution to journal › Article › peer-review

104 Citations (Scopus)

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.

Original language	English
Pages (from-to)	519-530
Number of pages	12
Journal	Cell Reports
Volume	15
Issue number	3
DOIs	https://doi.org/10.1016/j.celrep.2016.03.054
Publication status	Published - 2016 Apr 19

Bibliographical note

Funding Information:
We thank James Bradner and Jun Qi for providing JQ1. We thank R. Wysocki for assistance with microscopy. This work was supported by Cold Spring Harbor Laboratory NCI Cancer Center Support grant CA455087 for developmental funds and shared resource support. Additional funding was provided by the Alex’s Lemonade Stand Foundation and the V Foundation. J.-S.R. is supported by the Martin Sass Foundation and the Lauri Strauss Leukemia Foundation. A.S.B. is supported by NIH T32 GM008444 and NCI F30 CA186632. C.R.V. is supported by a Burroughs-Wellcome Fund Career Award, NIH grant NCI RO1 CA174793, and a Leukemia & Lymphoma Society Scholar Award.

Publisher Copyright:
© 2016 The Authors.

All Science Journal Classification (ASJC) codes

Biochemistry, Genetics and Molecular Biology(all)

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.celrep.2016.03.054

Cite this

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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.",

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note = "Funding Information: We thank James Bradner and Jun Qi for providing JQ1. We thank R. Wysocki for assistance with microscopy. This work was supported by Cold Spring Harbor Laboratory NCI Cancer Center Support grant CA455087 for developmental funds and shared resource support. Additional funding was provided by the Alex{\textquoteright}s Lemonade Stand Foundation and the V Foundation. J.-S.R. is supported by the Martin Sass Foundation and the Lauri Strauss Leukemia Foundation. A.S.B. is supported by NIH T32 GM008444 and NCI F30 CA186632. C.R.V. is supported by a Burroughs-Wellcome Fund Career Award, NIH grant NCI RO1 CA174793, and a Leukemia & Lymphoma Society Scholar Award. Publisher Copyright: {\textcopyright} 2016 The Authors.",

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N2 - 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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BET Bromodomain Inhibition Releases the Mediator Complex from Select cis-Regulatory Elements

Abstract

Bibliographical note

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UN SDGs

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