We are interested in factors controlling gene transcription, specifically epigenetic regulatory proteins. This includes the bromodomain family of epigenetic “reader” proteins and the sirtuin family of epigenetic “eraser” proteins, each of which interact with acylated lysine residues. Using drug-like chemical probes and targeted therapies, we dissect the roles of such proteins in autoimmune diabetes onset and progression.
BET BROMODOMAIN INHIBITORS DISRUPT A BRD4-p65 INTERACTION
Chronic inflammation in pancreatic islets is a key driver of damage that leads to eventual onset of type I autoimmune diabetes. We investigated the ability of BET bromodomain inhibitors to reduce pancreatic β-cell responsiveness to the proinflammatory cytokine IL-1β (Nord et al 2022). Indeed, this inhibition attenuated inflammatory mediator gene NOS2, consistent with inhibition of NF-kB. We used selective inhibitors of the first and second bromodomains of BRD4 and showed only the first bromodomain was necessary for interaction of the NF-kB p65 subunit with BRD4. This is the first study illustrating the therapeutic potential for specific bromodomain-targeted inhibitors in autoimmune diabetes.
Nord JA, Wynia-Smith SL, Gehant AL, Jones Lipinski RA, Naatz A, Rioja I, Kumar Prinja R, Corbett JA, Smith BC. N-terminal BET bromodomain inhibitors disrupt a BRD4-p65 interaction and reduce inducible nitric oxide synthase transcription in pancreatic ß-cells. Frontiers in Endocrinology. 2022. DOI: 10.3389/fendo.2022.923925.