1247-P: The SND1 Coregulator Controls ß-Cell Function and Identity

Abstract

Pancreatic β-cells are crucial for glucose-stimulated insulin secretion (GSIS) and whole-body glucose homeostasis. Dysfunctional β-cell mass results in diabetes mellitus (DM), a growing pandemic causing global economic burden. Pancreas-enriched transcription factors (TFs) highly expressed in the β-cell that coordinate expression of genes essential for normal β-cell function, are commonly disrupted in β-cells from diabetic individuals. Therefore, it is of considerable importance to understand how TFs function normally and the mechanisms driving their dysfunction in settings of diabetes. Pdx1, an essential TF involved in β-cell function and identity, recruits transcriptional coregulators to coordinate expression of gene expression programs throughout the β-cell. Here we focus on the Staphylococcal Nuclease and Tudor domain containing protein (SND1) coregulator, which has been shown in other cellular contexts to facilitate transcriptional control through the recruitment of chromatin modifying enzymes. By co-immunoprecipitation and proximity ligation assays, we have found Pdx1 and SND1 interact in rodent and human β-cell lines and tissues. We generated SND1 CRISPR/Cas9 knockout cell lines in the Min6 mouse β-cells (SND1-KO) and performed mRNA-sequencing. Genes linked to insulin secretion, (vitamin D receptor (VDR)), and maintenance of β-cell identity (SIX2) were found to be differentially expressed in SND1-KO cells. Glucose-stimulated insulin secretion (GSIS) in INS1 832/13 rat insulinoma cell lines is trending down following Snd1 knockdown (p = 0.15). Future studies include measuring GSIS under different stimulatory conditions in following knockdown of SND1 in primary mouse and human islets. Moreover, we will define the chromatin occupancy footprint of SND1 and explore if chromatin accessibility is altered in SND1-KO β-cell lines. Lastly, we will explore how interactions between Pdx1 and SND1 are altered in models of diabetes and human donor tissues. Disclosure S. Kanojia: None. R. K. Davidson: None. N. Casey: None. J. Spaeth: None. Funding National Institute of Diabetes and Digestive and Kidney Diseases (K01DK115633, P30DK097512)