85-OR: Swi/Snf Controls Transcriptional Programs Required for ß-Cell Development and Postnatal Islet Function

Abstract

A key feature of diabetes is insufficient functional β-cell mass. Strategies to augment functional β-cell mass include directed differentiation of stem cells towards a β-cell fate, which requires extensive knowledge of transcriptional programs governing differentiation in vivo. Pdx1, an essential transcription factor involved in β-cell differentiation, dynamically recruits coregulators to drive different gene expression programs. A recent study identified the ATP-dependent Swi/Snf chromatin remodeling complex as an important Pdx1-interacting partner. In the developing pancreas, conditional removal of the Brg Swi/Snf ATPase subunit compromised final pancreas mass, and loss of both ATPase subunits, Brg1 and Brm, led to glucose dyshomeostasis. While Swi/Snf is essential during early pancreas development and mature β-cell function, the role of Swi/Snf during endocrine cell development has yet to be explored. Here, we generated a conditional knockout of either Brg1 (Brg1ΔendoBrm+/-), Brm (Brg1Δendo/+Brm-/-), or both subunits (DKOΔendo) during endocrine development using Neurogenin 3 Cre. Four-week-old Brg1ΔendoBrm+/- mice are glucose intolerant, hyperglycemic, and hypoinsulinemic, with no phenotype observed in Brg1Δendo/+Brm-/-mice. Impaired glucose homeostasis of Brg1ΔendoBrm+/- mice was due in part to reduced islet number, impaired insulin secretion, and altered gene expression programs. DKOΔendo mice have not been found at weaning; however, postnatal day 6 DKOΔendo mice are severely hyperglycemic with reduced plasma insulin levels. Single-cell RNA-Seq of embryonic day 15.5 lineage-labeled cells revealed reduced insulin and glucagon transcript in the β-cell and α-cell clusters, respectively, in both Brg1ΔendoBrm+/- and DKOΔendo mice and reduced Neurogenin 3­ transcript in DKOΔendo endocrine progenitor clusters. These data suggest Swi/Snf plays a critical role in governing gene-expression programs essential for endocrine cell development. Disclosure R.K.Davidson: Employee; Eli Lilly and Company. S.Kanojia: None. M.E.Osmulski: None. J.Spaeth: None. Funding National Institutes of Health (R01DK129287, R03DK127129)