? cell dysfunction, induced by inflammation and other types of stress, is critical in pathogenesis of type 2 diabetes (T2D). Accordingly, strategies designed to protect ? cells from dysfunction could be attractive for combating diabetes. The candidate?s previous study identified that a ligand-dependent switch between vitamin D receptor (VDR)-associated bromodomain readers BRD9 and BRD7 regulates the anti-inflammatory response in ? cells. A combination of VDR activation and BRD9 inhibition promoted VDR-BRD7 association, suppressed inflammation in ? cells, and improved glucose homeostasis in multiple mouse T2D models. BRD9 and BRD7 belong to BAF and PBAF, respectively, two overlapping but functionally distinctive SWI/SNF chromatin remodeling complexes. Therefore, chromatin remodeling complexes may play essential roles in ? cell dysfunction in T2D. The hypothesis of this proposal is that the balance between BAF and PBAF complex, modulated by BRD9/BRD7, controls the ? cell epigenome and metabolic homeostasis. To investigate the gene-regulatory mechanisms associated with ? cell dysfunction, the studies proposed here will combine genomic, molecular and genetic approaches to pinpoint the role of SWI/SNF complexes in regulating the ? cell epigenome and function in T2D, in following specific aims:
Aim 1 : determine SWI/SNF complex balance in ? cells exposed to inflammatory cues by charting the genome distribution of key BAF and PBAF complex components;
Aim 2 : characterize SWI/SNF-mediated chromatin accessibility dynamics in shaping ? cell super enhancer activity;
Aim 3 : use ? cell specific knock-out mouse models to determine the roles and downstream targets of BRD9/BAF in vivo. Collectively, these studies may reveal how a fine-tuned balance between two competing chromatin remodeling complexes controls ? cell function in T2D, and may lead to novel strategies for the development of next generation anti-diabetic therapies directly targeting ? cell dysfunction. The candidate?s goal for the next three years is to develop an independent research program in the area of diabetes, nuclear receptors, and epigenetics, and to transition into an academic faculty position. He has extensive background training in transcription, epigenetics and metabolism. In the laboratory of Dr. Ronald Evans at the Salk Institute he continues to gain experience to understand transcriptional regulation and how it controls ? cell physiology. Dr. Mark Huising, an islet biologist, will serve as co-mentor and provide additional training in ? cell physiology and imaging. The candidate will continue to collaborate with his co-mentor, Dr. Diana Hargreaves, to acquire expertise in biochemical and genomic assays related to chromatin remodeling. The candidate?s long-term career goal is to become a leading independent biomedical researcher at an academic institution, investigating the molecular basis of diabetes and inflammation. This award will also allow him to develop his own research niche and distinguish himself from his current mentor.
Already a global epidemic, the incidence of T2D is expected to rapidly escalate in the coming decades. Understanding why and how ? cells fail is crucial for developing treatments. The research proposed here aims to better understand how SWI/SNF chromatin remodeling complexes control the epigenetic landscape in stressed ? cells.