174-OR: ADA Presidents’ Select Abstract: Epigenetic Regulation of Functional Beta-Cell Mass by Cohesin Smc3

Abstract

Both type 1 and type 2 diabetes are caused by insulin insufficiency due to inadequate functional beta-cell mass. The demise of beta-cells in diabetes is preceded by progressive impairment of beta-cell function. Several studies have shown that the regulation of beta-cell function and survival is tightly linked. However, the precise molecular mechanisms that link beta-cell function and survival remain far from clear. In this study, we report that the cohesin Smc3 is a novel epigenetic regulator of functional beta-cell mass. Smc3 is an ATPase that regulates the 3D chromatin architecture and chromatid cohesion, and plays an important role in cellular self-renewal, differentiation, and survival. Smc3 exists in a tripartite ring complex with proteins Smc1 and Rad21, and the association of this complex to the chromatin is regulated by Stag1. Our chromatin immunoprecipitation data suggest that the cohesin complex regulates beta-cell maturation and survival programs. Using transcriptomic profiling combined with histological and physiological analyses, we show that that the beta-cell specific Smc3 knockout mice (Smc3-BKO) become diabetic by 3 months of age, due to a progressive loss of beta-cell maturity and viability. Islets from the Smc3-BKO mice display impaired glucose stimulated insulin secretion (GSIS) around 1-2 months of age, with gene expression signatures that resemble functionally immature neonatal beta-cells. This is followed by progressive decline of beta-cell mass. At a molecular level, disruption of Smc3 leads to reduced protein levels of the other two subunits of the cohesin ring complex, Smc1 and Rad21. On the other hand, the mRNA levels of Stag1 are increased in the Smc3-BKO islets. Finally, we show that the cohesin regulatory program is disrupted in islets from humans with type 2 diabetes. Taken together, these studies provide a novel insight into the integrative epigenetic regulation of functional beta-cell mass. Disclosure J. K. Wang: None. A. Pandey: None. A. P. Ham: None. N. Parveen: None. S. Dhawan: None.