Gerald Denis, Ph.D.
Cancer Research Center
Ph.D.: University of California Berkeley
Mechanisms of Transcriptional Control Mediated Through the Activators and Chromatin Regulators Called Bromodomain Proteins
Our research elucidates mechanisms of transcriptional control mediated through a newly described class of co-activators and chromatin regulators called bromodomain proteins. A protein that we have newly characterized, Brd2, possesses tandem, mutually related bromodomains that are most similar in primary sequence to the bromodomain of the transcriptional co-activator CBP; yet in overall structural organization, most similar to the double bromodomains of TAFII250, which is an essential participant in the basal transcription machinery of all mammalian cells. Brd2 protein is ubiquitously expressed in mammalian tissues, and has homologs in yeast, Drosophila, Xenopus and other organisms, where these homologs play essential roles in development, including homeosis. In fibroblast models, we established a role for ras signaling in Brd2-dependent destabilization of cell cycle regulatory genes, particularly cyclin A. Chromatin immunoprecipitation establishes that Brd2 is present at the cyclin A promoter. In a transgenic (Tg) mouse model in which Brd2 constitutive expression is B lymphocyte-restricted, cyclin A transcription is upregulated even in resting Tg B cells; these cells also proliferate in vitro in response to mitogens at twice the rate of normal B cells. Over time, this phenotype in the mouse leads to deficiencies in adaptive immunity and to B cell lymphoma and leukemia. We are presently exploring a mechanism by which we hypothesize Brd2 overexpression destabilizes cyclin A: the protein probably provides a scaffold for a large nuclear complex that contains both E2F-1 and –2, a histone H4 specific acetyltransferase, TAFII250 and representatives of the Swi/Snf complex. Both direct recruitment of E2Fs and chromatin remodeling are known to control transcription at the cyclin A promoter as well as other cyclin genes, but details are lacking. The Tg B cell system therefore represents a unique opportunity to study this scaffold hypothesis and the molecular mechanisms of proliferation and malignancy. In translational studies, we also use this model to identify new targets for immunological and anti-cancer pharmaceutical agents.
Phone: 617-414-1371; Fax: 617-638-5609