Biochemical mechanisms of beta cell protection through bromodomain inhibition

PROJECT SUMMARY Type 1 diabetes (T1D) is an autoimmune disease characterized by insulin deficiency resulting from reduced function and progressive loss of insulin-producing pancreatic β-cells. Although many T-cell-dependent mechanisms underlie T1D progression, the role of the β-cell responses in promoting autoimmune inflammation is poorly understood. Our long-range goals are to determine the role of the three ubiquitously expressed bromodomain and extraterminal (BET) family members (BRD2/3/4) in β-cell transcriptional responses to inflammation associated with autoimmune diabetes. Each BET protein contains two bromodomains, which are epigenetic ‘readers’ of lysine acetylation on histones and transcription factors, and bromodomain binding to acetylated histones/proteins regulates transcription in a gene- and cell-type dependent manner. Interestingly, pan inhibitors that equally target both bromodomains of all BET proteins elicit broad anti-inflammatory effects and delay diabetes onset in the non-obese diabetic T1D mouse model. However, the direct effects of BET bromodomain inhibitors on the function and viability of β-cells are largely unknown. We hypothesize that β-cell inflammation (Aim 1) and identity (Aim 2) can be regulated by selectively inhibiting BET proteins in a bromodomain- and cell-type-specific manner. Broad inhibition of all BET bromodomains and the inability to directly target specific cell types are significant challenges, and such broad inhibition is associated with dose- limiting toxicities and adverse effects. We will address these limitations by evaluating the transcriptional actions of next-generation BET bromodomain inhibitors that are selective for a subset of BET bromodomains (Aim 1 and 2) and develop innovative methods to selectively target BET bromodomain inhibitors to β cells (Aim 3). Completing these aims will uncover the precise gene- and cell-type-specific mechanisms by which BET bromodomain inhibition modulates β-cell transcription, inform the development of next-generation β-cell targeted inhibitors, and advance T1D treatment and β-cell replacement strategies.