ISL1 controls pancreatic alpha cell fate and regulates beta cell differentiation and maturation [RNA-seq]. ISL1 controls pancreatic alpha cell fate and regulates beta cell differentiation and maturation [RNA-seq]

Glucose homeostasis is dependent on functional pancreatic α and ß cells. Mechanisms underlying generation and maturation of these endocrine cells remain unclear. Here, we unravel the molecular mode of action of ISL1 in controlling α cell fate and endocrine differentiation in the pancreas. By combining transgenic mouse models, transcriptomic and epigenomic profiling, we uncover that elimination of Isl1 results in a diabetic phenotype with a complete loss of α cells, disrupted pancreatic islet architecture, downregulation of maturation markers of ß cells, and an enrichment in an intermediate endocrine progenitor transcriptomic profile. Mechanistically, apart from the altered transcriptome of pancreatic endocrine cells, Isl1 elimination results in altered silencing H3K27me3 histone modifications in the promoter regions of the essential genes for endocrine cell differentiation. Our results thus show that ISL1 transcriptionally and epigenetically controls α cell fate competence, and ß cell maturation, suggesting that ISL1 is a critical component for generating functional α and ß cells. Overall design: Together 22 samples of 100 FACS-sorted tdTomato+ endocrine cells were analyzed. 11 samples of P9 (biological replicates of 5 control and 6 mutant samples) and 11 samples of E14.5 (biological replicates of 6 control and 5 mutant samples) were analyzed separately.

葡萄糖稳态依赖于功能正常的胰腺α细胞与β细胞。目前这类内分泌细胞的生成与成熟机制仍未明确。本研究解析了ISL1在调控胰腺α细胞命运与内分泌细胞分化过程中的分子作用机制。通过结合转基因小鼠模型、转录组学与表观基因组学分析，本研究发现敲除Isl1会导致小鼠出现糖尿病表型，具体表现为α细胞完全缺失、胰岛结构紊乱、β细胞成熟标志物表达下调，且中间型内分泌祖细胞的转录组特征显著富集。从机制层面来看，除胰腺内分泌细胞的转录组发生改变外，敲除Isl1还会导致内分泌细胞分化必需基因启动子区域的H3K27me3组蛋白沉默修饰出现异常。综上，本研究结果表明ISL1可在转录与表观层面调控α细胞的命运潜能以及β细胞的成熟过程，提示ISL1是生成功能正常的α与β细胞的关键调控元件。实验设计概述：本研究共分析22份样本，每份样本均来自100个经FACS（荧光激活细胞分选）分选的tdTomato阳性内分泌细胞。其中，P9（出生后第9天）时期的样本共11份，包含5个对照组与6个突变组的生物学重复；E14.5（胚胎第14.5天）时期的样本共11份，包含6个对照组与5个突变组的生物学重复，两组样本分别独立分析。