Anand S. Bhagwat
B.A. M.S. University of Pennsylvania, 2009
7th Year MSTP
3rd Year Molecular Genetics & Microbiology Medical Student
Advisor: Christopher Vakoc, PhD
Department: Cold Spring Harbor Laboratory
Graduate Program: Molecular Genetics & Microbiology
Title: Mediator is a key effector of Brd4-dependent oncogenic transcription
Abstract :
BET bromodomain inhibition has proven a viable therapeutic modality in a wide range of malignancies. In particular, targeting Brd4 with small molecule inhibitors such as JQ1 leads to cell-cycle arrest, apoptosis, and terminal differentiation of acute myeloid leukemia (AML) blasts, and a significant prolonging of survival in mice with AML. These findings have led to successful Phase I clinical trials of BET bromodomain inhibition. Many key downstream transcriptional targets of Brd4, such as Myc, have been identified, but exactly how Brd4 regulates these genes is unclear. Brd4 is known to interact with a number of protein complexes, any of which might represent key intermediaries of Brd4’s regulation of oncogenic transcription. One of these, Mediator, is a conserved coactivator complex comprised of 30 proteins. The nature of Brd4Mediator interactions, however, remains to be explored. Here, we show that Brd4 and Mediator co-localize across the genome and that Mediator is dependent on Brd4 for its occupancy on chromatin. We further show through functional genetic screens that a subset of Mediator subunits is required for the maintenance of AML and that depletion of these subunits from AML cells phenocopies inhibition of Brd4, suggesting a functional relevance to the Brd4-Mediator interaction. These findings identify Mediator as a key effector of Brd4 activity in AML, highlight its dependence on Brd4 for chromatin occupancy, and nominate the Mediator complex as a potential therapeutic target in AML.
Publications:
(pre-MSTP publications indicated with an *)
Bhagwat AS, Roe JS, Mok BYL, Hohmann AF, Shi J, Vakoc CR Cell Reports. 2016, 15(3):519-530 BET Bromodomain Inhibition Releases the Mediator Complex from Select cis-Regulatory Elements
Bhagwat AS, Vakoc CR Trends in Cancer. 2015, 1(1):53-65 Targeting Transcription Factors in Cancer. Bhagwat AS, Roe JS, Mok BYL, Hohmann AF, Shi J, Vakoc CR Cell Reports. 2016, 15(3):519-530 BET Bromodomain Inhibition Releases the Mediator Complex from Select cis-Regulatory Elements
*Hojun Li, Virginia Haurigot, Yannick Doyon, Tianjian Li, Sunnie Y. Wong, Anand S. Bhagwat, Nirav Malani, Xavier M. Anguela, Rajiv Sharma, Lacramiora Ivanciu, Samuel L. Murphy, Jonathan D. Finn, Fayaz R. Khazi, Shangzhen Zhou, David E. Paschon, Edward J. Rebar, Frederic D. Bushman, Philip D. Gregory, Michael C. Holmes& Katherine A. High. (2011). In vivo genome editing restores haemostasis in a mouse model of haemophilia. Nature.
*Murphy SL, Bhagwat A, Edmonson S, Zhou S, High KA. (2008). High-throughput screening and biophysical interrogation of hepatotropic AAV. Mol Ther. 16(12):1960-7. PMID:18827805.
