¿ 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.