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.