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

Strategies to augment functional -cell mass include directed differentiation of stem cells towards a -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 -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, - and -cell clusters, highlighting a critical role for Swi/Snf in governing gene-expression programs essential for endocrine cell development.扩增功能细胞团块的策略包括将干细胞定向诱导分化为β细胞谱系，该过程需充分掌握体内调控内分泌祖细胞分化的转录程序。本文阐述了Swi/Snf染色质重塑复合体（Swi/Snf chromatin remodeling complex）的Brg1与Brm ATP酶亚基在内分泌细胞发育中的调控作用。本研究借助转基因敲除动物模型，发现内分泌祖细胞中Brg1的条件性敲除会引发血糖稳态失调、胰岛团块与功能受损；而完全丧失Swi/Snf复合体活性（即同时敲除Brg1与Brm）则会因严重高血糖导致产后早期死亡，并伴随β细胞团块减少。对胚胎第15.5天谱系标记细胞开展的单细胞RNA测序（Single-cell RNA Sequencing）结果显示，已定向内分泌的β细胞与α细胞簇中，成熟标志物、增殖相关基因及激素的表达水平均出现下调，这凸显了Swi/Snf复合体在调控内分泌细胞发育必需的基因表达程序中的关键作用。