PhD Department of Oncological Sciences
Howard Hughes Medical Institute
Phone: (801) 585-1823
I am interested in how chromatin-remodeling complexes are targeted to specific chromatin regions and how binding is regulated. It has been proposed that distinct patterns of histone modification function as a histone code for the recruitment of chromatin-remodeling complexes. The bromodomain (BD) recognizes acetylated lysine residues and may enable remodelers to bind to acetylated nucleosomes. Rsc4 is an essential double bromodomain protein in the yeast RSC remodeling complex and both its bromodomains are required for Rsc4 function. Using a combination of genetics and biochemistry we’ve determined that Rsc4 BD2 recognizes histone H3 Lys14ac. Intriguingly, we find that the amino terminus of Rsc4 is specifically acetylated at Lys25 in vitro and in vivo by the acetyltransferase Gcn5, and this is a ligand for Rsc4 BD1. We also find that binding of Rsc4 BD1 to Rsc4 Lys25ac functions in an autoinhibitory manner and interferes with BD2 binding to H3 Lys14ac. This is the first autoregulatory mechanism described for paired bromodomains. Based on our genetic analysis we propose that there are other unknown ligands for BD1 and possibly BD2. We are actively searching for these additional ligands. I am also currently developing an assay to analyze factors critical for RSC recruitment in vivo.