Gerald V. Denis, Ph.D.
Scientific co-Director, Flow Cytometry Core
Faculty Member: Graduate Program in Molecular Medicine, Hematology Training Program, Boston Nutrition Obesity Research Center
A.B. Harvard College
M.Sc. University of Tokyo
Ph.D. University of California, Berkeley
We are interested in chromatin and co-activator control of transcription. Our lab first reported the function of a double bromodomain-containing transcriptional co-activator called Brd2. When expressed constitutively in the B cells of transgenic mice, Brd2 associates with E2F proteins and the SWI/SNF complex, altering chromatin status and transactivating the cyclin A gene. Increased cyclin A levels destabilize the cell cycle and cause B cell lymphoma and leukemia. We are actively engaged in elucidating the Brd2-specific transcriptional functions that have this major impact on B cell development and proliferation. A logical next step in the study of Brd2 function was to delete it in mice, and given its ubiquitous expression as a transcriptional co-activator, we had expected Brd2 deficient mice to be nonviable. However, to our great surprise, the animals became extremely obese. Even more remarkably, they avoided inflammation-associated insulin resistance and Type 2 diabetes, despite incredible adiposity and body weights of nearly 100 g. In fact, upon glucose challenge, severely obese brd2 lo mice clear glucose even better than wild type. It was immediately apparent to us that, by uncoupling obesity from inflammation and diabetes, these mice reveal a novel mechanism to explain ‘metabolically healthy but obese’ people, who (unlike the majority of the obese population) have a reduced inflammatory profile and are protected from Type 2 diabetes. Brd2-deficient macrophages underproduce TNF-alpha and other pro-inflammatory cytokines; thus, the mild immunodeficiency we see offers an unexpected and novel mechanism linking immune function to insulin resistance and diabetes in humans, suggesting new avenues for treatment of obesity.
- Wang F, H Liu, WP Blanton, A Belkina, NK LeBrasseur and GV Denis (2010). Brd2 disruption in mice causes severe obesity without type 2 diabetes. Biochem J. 425:71–83. Published online 2 November 2009. PMID: 19883376
- Romesser PB, DH Perlman, DV Faller, CE Costello, ME McComb and GV Denis (2009). Development of a malignancy-associated proteomic signature for diffuse large B cell lymphoma. Am. J. Pathol. 175: 25–35. PMID: 19498000, PMC2708791
- Longe H, PB Romesser, A Rankin, DV Faller, MS Eller, BA Gilchrest and GV Denis (2009). Telomere homolog oligonucleotides induce apoptosis in malignant but not in normal lymphoid cells: Mechanism and therapeutic potential. Int. J. Cancer. 124:473–482.
- Lenburg M, A Sinha, DV Faller and GV Denis (2007). Tumor-specific and proliferation-specific gene expression typifies murine transgenic B cell lymphomagenesis. J. Biol. Chem. 282: 4803–4811.
- You J, V Srinivasan, GV Denis, WJ Harrington Jr, ME Ballestas, KM Kaye and PM Howley (2006). Kaposi’s Sarcoma-associated herpesvirus latency-associated nuclear antigen interacts with bromodomain protein Brd4 on host mitotic chromosomes. J. Virol. 80: 8909–8919. PMC1563901
- Denis GV, ME McComb, DV Faller, A Sinha, PB Romesser and CE Costello (2006). Identification of transcription complexes that contain the double bromodomain protein Brd2 and chromatin remodeling machines. J. Proteome Res. 5: 502–511. PMID: 16512664
- Sinha A, DV Faller and GV Denis (2005). Bromodomain analysis of Brd2-dependent transcriptional activation of cyclin A. Biochem. J. 387: 257–269. PMID: 15548137, PMC1134954
- Greenwald R, JR Tumang, A Sinha, N Currier, RD Cardiff, TL Rothstein, DV Faller and GV Denis (2004). Em-BRD2 transgenic mice develop B cell lymphoma and leukemia. Blood 103: 1475–1484. PMID: 14563639