All of the work in my lab is focused on the study of a novel transcriptional co-activator, the double bromodomain protein Brd2, which I discovered as a postdoc (Denis & Green 1996 Genes Dev. 10). This protein is related to the basal transcription factor TAFII250; Brd2 binds to acetylated histones through its bromodomains, then recruits transcription factors and co-activators/co-repressors to promoter chromatin. Through its association with the SWI/SNF complex, Brd2 helps remodel chromatin to regulate transcription activity (Denis et al. 2000 Cell Growth Diff. 11; Guo et al. 2000 J. Cell Sci. 113; Denis et al. 2006 J. Proteome Res. 5). This highly conserved and ubiquitous protein is essential for life; knockout of the gene is lethal in all organisms tested so far (mice, Drosophila, yeast). We have used American Cancer Society and NCI funding to discover that, in mammals, two key targets of Brd2 are the cyclin A locus (Sinha et al. 2005 Biochem. J. 387), which controls cell cycle progression through S phase, and gene targets of the PPARgamma transcription factor, which controls adipogenic transcription. Brd2 is a positive regulator of proliferation but a negative regulator of adipogenesis. In transgenic mice that constitutively express Brd2 in B cells, cyclin A is upregulated and the cell cycle is destabilized, leading to an aggressive non-Hodgkin’s lymphoma (Greenwald et al. 2004 Blood 103). We are using new funding from the NCI to develop novel transcriptional and proteomic profiling of this and related human malignancies, as well as to identify new drug targets and develop original therapeutic approaches for its treatment (Longe et al. 2005 Blood 106; Lenburg et al. 2007 J. Biol. Chem. 282; Longe et al. 2007 Proc. Am. Assoc. Cancer Res. 2007; Longe et al. 2008 Int. J. Cancer; Romesser et al. 2008. Am. J. Pathol.). Meanwhile, whole-animal knockdown of Brd2 in mice causes extreme, morbid obesity; dramatically illustrating an unexpected role for Brd2 in energy homeostasis. With new, pilot funding from the Boston Area Diabetes and Endocrinology Research Center, we have shown that brd2 knockdown mice are hyperinsulinemic, yet never become diabetic, and exhibit hypoglycemia and better glucose tolerance than wild type. Furthermore, Brd2 associates with PPARgamma and alters adipogenesis from 3T3-L1 pre-adipocytes; Brd2 opposes PPARgamma transcriptional activation, suggesting Brd2 plays a novel, crucial negative regulatory role in adipogenesis (Wang et al. 2008 Genes Dev.). Finally, we have recently reconstituted the murine immune system with hematopoietic stem cells transduced with lentiviruses for Brd2 overexpression or shRNA knockdown, and learned that Brd2 expression causes a dramatic expansion of the lymphoid compartment and B cell hypersensitivity to mitogens, nicely recapitulating the transgenic model, whereas Brd2 knockdown completely blocks lymphoid development, suggesting that this factor plays a crucial and fundamental role in normal immune biology and the processes of adaptive immunity.
- Associate Professor, Pharmacology & Experimental Therapeutics, Boston University School of Medicine
- Center Faculty Member, Cancer Research Center, Boston University School of Medicine
- Graduate Faculty (Primary Mentor of Grad Students), Boston University School of Medicine, Division of Graduate Medical Sciences
- University of California, Berkeley, PhD
- University of Tokyo, MSc
- Harvard College, AB
- Published on 11/15/2017
Palmer JR, Castro-Webb N, Bertrand K, Bethea TN, Denis GV. Type II Diabetes and Incidence of Estrogen Receptor Negative Breast Cancer in African American Women. Cancer Res. 2017 Nov 15; 77(22):6462-6469. PMID: 29141994.
- Published on 8/25/2017
Denis GV, Sebastiani P, Andrieu G, Tran AH, Strissel KJ, Lombardi FL, Palmer JR. Relationships Among Obesity, Type 2 Diabetes, and Plasma Cytokines in African American Women. Obesity (Silver Spring). 2017 Nov; 25(11):1916-1920. PMID: 28840653.
- Published on 4/13/2017
Denis GV, Palmer JR. "Obesity-Associated" Breast Cancer in Lean Women: Metabolism and Inflammation as Critical Modifiers of Risk. Cancer Prev Res (Phila). 2017 May; 10(5):267-269. PMID: 28408379.
- Published on 12/19/2016
Charlot M, Castro-Webb N, Bethea TN, Bertrand K, Boggs DA, Denis GV, Adams-Campbell LL, Rosenberg L, Palmer JR. Diabetes and breast cancer mortality in Black women. Cancer Causes Control. 2017 Jan; 28(1):61-67. PMID: 27995352.
- Published on 9/20/2016
Andrieu G, Tran AH, Strissel KJ, Denis GV. BRD4 Regulates Breast Cancer Dissemination through Jagged1/Notch1 Signaling. Cancer Res. 2016 Nov 15; 76(22):6555-6567. PMID: 27651315.
- Published on 9/13/2016
Strissel KJ, Nicholas DA, Castagne-Charlotin M, Ko N, Denis GV. Correction to "Barriers to Obtaining Sera and Tissue Specimens of African-American Women for the Advancement of Cancer Research". Clin Med Insights Womens Health. 2016; 9:35. PMID: 27695380.
- Published on 8/4/2016
Nicholas DA, Andrieu G, Strissel KJ, Nikolajczyk BS, Denis GV. BET bromodomain proteins and epigenetic regulation of inflammation: implications for type 2 diabetes and breast cancer. Cell Mol Life Sci. 2017 Jan; 74(2):231-243. PMID: 27491296.
- Published on 7/21/2016
Andrieu G, Belkina AC, Denis GV. Clinical trials for BET inhibitors run ahead of the science. Drug Discov Today Technol. 2016 Mar; 19:45-50. PMID: 27769357.
- Published on 7/14/2016
Strissel KJ, Nicholas DA, Castagne-Charlotin M, Ko N, Denis GV. Barriers to Obtaining Sera and Tissue Specimens of African-American Women for the Advancement of Cancer Research. Clin Med Insights Womens Health. 2016; 9(Suppl 1):57-61. PMID: 27441007.
- Published on 3/23/2016
Deeney JT, Belkina AC, Shirihai OS, Corkey BE, Denis GV. BET Bromodomain Proteins Brd2, Brd3 and Brd4 Selectively Regulate Metabolic Pathways in the Pancreatic ß-Cell. PLoS One. 2016; 11(3):e0151329. PMID: 27008626.
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