Epigenetic dosage identifies two major and functionally distinct j3 cell subtypes
Epigenetic dosage identifies two major and functionally distinct j3 cell subtypes
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DOI：
10.1016/j.cmet.2023.03.008
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发表时间：
2023-05-02
期刊：
影响因子：
29
通讯作者：
Pospisilik, John Andrew
中科院分区：
文献类型：
--
作者：
Dror, Erez;Fagnocchi, Luca;Pospisilik, John Andrew
指定和稳定细胞亚型的机制仍然知之甚少。在这里，我们根据组蛋白标记的异质性确定了两种主要的胰腺J3细胞亚型(j3HI和j3LO)。J3HI细胞表现出-4倍高水平的H3K27me3，明显的染色质组织和紧凑，以及特定的转录模式。J3HI和J3LO细胞在大小、形态、胞质和细胞核超微结构、表观基因组、细胞表面标志物的表达和功能等方面也存在差异，可将其分为CD24+和CD24-组分。在功能上，j3HI细胞在体内和体外都增加了线粒体的质量、活性和胰岛素的分泌。部分功能丧失提示H3K27me3剂量在体内调节j3HI/j3LO比率，提示J3细胞亚型同一性和比率的控制至少部分解偶联。这两种亚型在人类中都是保守的，而j3HI细胞在患有2型糖尿病的人中丰富。因此，表观遗传剂量是细胞亚型规范的一种新的调节因素，并识别两种功能上不同的J3细胞亚型。
The mechanisms that specify and stabilize cell subtypes remain poorly understood. Here, we identify two ma-jor subtypes of pancreatic j3 cells based on histone mark heterogeneity (j3HI and j3LO). j3HI cells exhibit -4-fold higher levels of H3K27me3, distinct chromatin organization and compaction, and a specific transcriptional pattern. j3HI and j3LO cells also differ in size, morphology, cytosolic and nuclear ultrastructure, epigenomes, cell surface marker expression, and function, and can be FACS separated into CD24+ and CD24- fractions. Functionally, j3HI cells have increased mitochondrial mass, activity, and insulin secretion in vivo and ex vivo. Partial loss of function indicates that H3K27me3 dosage regulates j3HI/j3LO ratio in vivo, suggesting that con-trol of j3 cell subtype identity and ratio is at least partially uncoupled. Both subtypes are conserved in humans, with j3HI cells enriched in humans with type 2 diabetes. Thus, epigenetic dosage is a novel regulator of cell subtype specification and identifies two functionally distinct j3 cell subtypes.