The Swi/Snf chromatin remodeling complex regulates pancreatic endocrine cell expansion and differentiation in vivo

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 endocrine progenitor cell differentiation in vivo. Here we describe the contributions of the Brg1 and Brm ATPase subunits of the Swi/Snf chromatin remodeling complex on endocrine cell development. Through the use of transgenic knockout animal models we reveal that conditional knockout of Brg1 in endocrine progenitors results in blood glucose dysregulation, reduced islet mass and function, while loss of all Swi/Snf activity (Brg1 and Brm) results in early postnatal death, resulting from severe hyperglycemia and reduced β-cell mass. Single-cell RNA Sequencing of embryonic day 15.5 lineage-labeled cells revealed reduced expression of maturation markers, proliferation genes, and hormones in endocrine-committed, β- and α-cell clusters, highlighting a critical role for Swi/Snf in governing gene-expression programs essential for endocrine cell development.