Keywords
Last Name

Gerald V. Denis, PhD

TitleAssociate Professor
InstitutionBoston University School of Medicine
DepartmentMedicine
DivisionHematology & Medical Oncology
Address72 E. Concord St
Boston MA 02118
Phone(617) 414-1371
ORCID ORCID Icon0000-0001-9886-0401
Other Positions
TitleGraduate Faculty (Primary Mentor of Grad Students)
InstitutionBoston University School of Medicine, Graduate Medical Sciences

TitleAssociate Professor
InstitutionBoston University School of Medicine
DepartmentPharmacology & Experimental Therapeutics

 Research Expertise & Professional Interests
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.

 Self-Described Keywords
  • cell cycle
  • hematologic malignancy
  • immunology
  • inflammation
  • mouse models
  • obesity
  • stem cells
  • tumor suppressors
 Publications
Publications listed below are automatically derived from MEDLINE/PubMed and other sources, which might result in incorrect or missing publications. Faculty can login to make corrections and additions.
List All   |   Timeline
  1. Goodson JM, Kantarci A, Hartman ML, Denis GV, Stephens D, Hasturk H, Yaskell T, Vargas J, Wang X, Cugini M, Barake R, Alsmadi O, Al-Mutawa S, Ariga J, Soparkar P, Behbehani J, Behbehani K, Welty F. Metabolic disease risk in children by salivary biomarker analysis. PLoS One. 2014; 9(6):e98799.
    View in: PubMed
  2. Belkina AC, Blanton WP, Nikolajczyk BS, Denis GV. The double bromodomain protein Brd2 promotes B cell expansion and mitogenesis. J Leukoc Biol. 2014 Mar; 95(3):451-60.
    View in: PubMed
  3. Chung J, Karkhanis V, Tae S, Yan F, Smith P, Ayers LW, Agostinelli C, Pileri S, Denis GV, Baiocchi RA, Sif S. Protein Arginine Methyltransferase 5 (PRMT5) Inhibition Induces Lymphoma Cell Death through Reactivation of the Retinoblastoma Tumor Suppressor Pathway and Polycomb Repressor Complex 2 (PRC2) Silencing. J Biol Chem. 2013 Dec 6; 288(49):35534-47.
    View in: PubMed
  4. Denis GV, Hamilton JA. Healthy obese persons: how can they be identified and do metabolic profiles stratify risk? Curr Opin Endocrinol Diabetes Obes. 2013 Oct; 20(5):369-76.
    View in: PubMed
  5. DeFuria J, Belkina AC, Jagannathan-Bogdan M, Snyder-Cappione J, Carr JD, Nersesova YR, Markham D, Strissel KJ, Watkins AA, Zhu M, Allen J, Bouchard J, Toraldo G, Jasuja R, Obin MS, McDonnell ME, Apovian C, Denis GV, Nikolajczyk BS. B cells promote inflammation in obesity and type 2 diabetes through regulation of T-cell function and an inflammatory cytokine profile. Proc Natl Acad Sci U S A. 2013 Mar 26; 110(13):5133-8.
    View in: PubMed
  6. Belkina AC, Nikolajczyk BS, Denis GV. BET protein function is required for inflammation: Brd2 genetic disruption and BET inhibitor JQ1 impair mouse macrophage inflammatory responses. J Immunol. 2013 Apr 1; 190(7):3670-8.
    View in: PubMed
  7. Wang F, Deeney JT, Denis GV. Brd2 gene disruption causes "metabolically healthy" obesity: epigenetic and chromatin-based mechanisms that uncouple obesity from type 2 diabetes. Vitam Horm. 2013; 91:49-75.
    View in: PubMed
  8. Denis GV, Obin MS. 'Metabolically healthy obesity': origins and implications. Mol Aspects Med. 2013 Feb; 34(1):59-70.
    View in: PubMed
  9. Nikolajczyk BS, Jagannathan-Bogdan M, Denis GV. The outliers become a stampede as immunometabolism reaches a tipping point. Immunol Rev. 2012 Sep; 249(1):253-75.
    View in: PubMed
  10. Banerjee C, Archin N, Michaels D, Belkina AC, Denis GV, Bradner J, Sebastiani P, Margolis DM, Montano M. BET bromodomain inhibition as a novel strategy for reactivation of HIV-1. J Leukoc Biol. 2012 Dec; 92(6):1147-54.
    View in: PubMed
  11. Belkina AC, Denis GV. BET domain co-regulators in obesity, inflammation and cancer. Nat Rev Cancer. 2012 Jul; 12(7):465-77.
    View in: PubMed
  12. Ehrlich DJ, McKenna BK, Evans JG, Belkina AC, Denis GV, Sherr DH, Cheung MC. Parallel imaging microfluidic cytometer. Methods Cell Biol. 2011; 102:49-75.
    View in: PubMed
  13. Denis GV. Bromodomain coactivators in cancer, obesity, type 2 diabetes, and inflammation. Discov Med. 2010 Dec; 10(55):489-99.
    View in: PubMed
  14. Belkina AC, Denis GV. Obesity genes and insulin resistance. Curr Opin Endocrinol Diabetes Obes. 2010 Oct; 17(5):472-7.
    View in: PubMed
  15. Denis GV, Nikolajczyk BS, Schnitzler GR. An emerging role for bromodomain-containing proteins in chromatin regulation and transcriptional control of adipogenesis. FEBS Lett. 2010 Aug 4; 584(15):3260-8.
    View in: PubMed
  16. Wang F, Liu H, Blanton WP, Belkina A, Lebrasseur NK, Denis GV. Brd2 disruption in mice causes severe obesity without Type 2 diabetes. Biochem J. 2010 Jan 1; 425(1):71-83.
    View in: PubMed
  17. Romesser PB, Perlman DH, Faller DV, Costello CE, McComb ME, Denis GV. Development of a malignancy-associated proteomic signature for diffuse large B-cell lymphoma. Am J Pathol. 2009 Jul; 175(1):25-35.
    View in: PubMed
  18. Longe HO, Romesser PB, Rankin AM, Faller DV, Eller MS, Gilchrest BA, Denis GV. Telomere homolog oligonucleotides induce apoptosis in malignant but not in normal lymphoid cells: mechanism and therapeutic potential. Int J Cancer. 2009 Jan 15; 124(2):473-82.
    View in: PubMed
  19. Lenburg ME, Sinha A, Faller DV, Denis GV. Tumor-specific and proliferation-specific gene expression typifies murine transgenic B cell lymphomagenesis. J Biol Chem. 2007 Feb 16; 282(7):4803-11.
    View in: PubMed
  20. You J, Srinivasan V, Denis GV, Harrington WJ, Ballestas ME, Kaye KM, Howley PM. Kaposi's sarcoma-associated herpesvirus latency-associated nuclear antigen interacts with bromodomain protein Brd4 on host mitotic chromosomes. J Virol. 2006 Sep; 80(18):8909-19.
    View in: PubMed
  21. Denis GV, McComb ME, Faller DV, Sinha A, Romesser PB, Costello CE. Identification of transcription complexes that contain the double bromodomain protein Brd2 and chromatin remodeling machines. J Proteome Res. 2006 Mar; 5(3):502-11.
    View in: PubMed
  22. Sinha A, Faller DV, Denis GV. Bromodomain analysis of Brd2-dependent transcriptional activation of cyclin A. Biochem J. 2005 Apr 1; 387(Pt 1):257-69.
    View in: PubMed
  23. Greenwald RJ, Tumang JR, Sinha A, Currier N, Cardiff RD, Rothstein TL, Faller DV, Denis GV. E mu-BRD2 transgenic mice develop B-cell lymphoma and leukemia. Blood. 2004 Feb 15; 103(4):1475-84.
    View in: PubMed
  24. Denis GV, Yu Q, Ma P, Deeds L, Faller DV, Chen CY. Bcl-2, via its BH4 domain, blocks apoptotic signaling mediated by mitochondrial Ras. J Biol Chem. 2003 Feb 21; 278(8):5775-85.
    View in: PubMed
  25. Peulen O, Denis G, Defresne MP, Dandrifosse G. Spermine-Induced alteration of small intestine in suckling rat: involvement of apoptosis or Zn2+ enzymes? Dig Dis Sci. 2001 Nov; 46(11):2490-8.
    View in: PubMed
  26. Denis GV. Bromodomain motifs and "scaffolding"? Front Biosci. 2001 Sep 1; 6:D1065-8.
    View in: PubMed
  27. Denis GV. Duality in bromodomain-containing protein complexes. Front Biosci. 2001 Aug 1; 6:D849-52.
    View in: PubMed
  28. Verlaet M, Deregowski V, Denis G, Humblet C, Stalmans MT, Bours V, Castronovo V, Boniver J, Defresne MP. Genetic imbalances in preleukemic thymuses. Biochem Biophys Res Commun. 2001 Apr 27; 283(1):12-8.
    View in: PubMed
  29. Guo N, Faller DV, Denis GV. Activation-induced nuclear translocation of RING3. J Cell Sci. 2000 Sep; 113 ( Pt 17):3085-91.
    View in: PubMed
  30. Denis GV, Vaziri C, Guo N, Faller DV. RING3 kinase transactivates promoters of cell cycle regulatory genes through E2F. Cell Growth Differ. 2000 Aug; 11(8):417-24.
    View in: PubMed
  31. Humblet C, Denis G, Greimers R, Boniver J, Defresne MP. Apoptosis during the development of radiogenic thymic lymphomas: effects of treatments inhibiting lymphoma development. Anticancer Res. 1998 Sep-Oct; 18(5A):3469-74.
    View in: PubMed
  32. Ostrowski J, Florio SK, Denis GV, Suzuki H, Bomsztyk K. Stimulation of p85/RING3 kinase in multiple organs after systemic administration of mitogens into mice. Oncogene. 1998 Mar 5; 16(9):1223-7.
    View in: PubMed
  33. Denis GV, Green MR. A novel, mitogen-activated nuclear kinase is related to a Drosophila developmental regulator. Genes Dev. 1996 Feb 1; 10(3):261-71.
    View in: PubMed
  34. Tegge W, Denis GV, Ballou CE. Synthesis and Ca(2+)-release activity of D- and L-myo-inositol 2,4,5-trisphosphate and D- and L-chiro-inositol 1,3,4-trisphosphate. Carbohydr Res. 1991 Sep 18; 217:107-16.
    View in: PubMed
  35. Denis GV, Ballou CE. The Ca2+ release activities of D-myo-inositol 1,4,5-trisphosphate analogs are quantized. Cell Calcium. 1991 Jun; 12(6):395-401.
    View in: PubMed
  36. Denis GV, Toyoshima S, Osawa T. Concanavalin A- and calcium-dependent phosphorylation of a protein of 80 kDa in mouse lymphocytes rendered permeable to exogenously added [gamma-32P]ATP. Biochim Biophys Acta. 1986 Feb 21; 885(2):136-45.
    View in: PubMed
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