ISL1限制了原始细胞程序并促进β细胞成熟,揭示了糖尿病进展中的性别差异
Valeria Fabriciova1,2, Romana Bohuslavova1, Laura Lebron-Mora1,2
1Laboratory of Molecular Pathogenetics, Institute of Biotechnology, Czech Academy of Sciences (CAS), Prague, Czechia.
Diabetes
|February 17, 2026
概括
转录因子ISL1对于胰腺内分泌细胞的成熟和功能至关重要. 失去了ISL1导致不成熟的β细胞和受损的α细胞,导致糖尿病的发展.
科学领域:
- 内分泌学 在内分泌学.
- 发展生物学 发展生物学
- 分子遗传学 分子遗传学
背景情况:
- 胰腺小岛细胞通过受调节的转录和表观遗传过程从祖先池中发展.
- 转录因子ISL1 (ISL LIM主体) 对于小岛的发育至关重要,但其精确的分子功能尚不清楚.
- ISL1与糖尿病易感性有关,但其在胰腺内分泌成熟中的作用仍未解决.
研究的目的:
- 阐明ISL1在维持胰腺内分泌细胞同一性和终端分化方面的分子功能.
- 研究胰腺内分泌前体中ISL1损失的转录和表观遗传后果.
- 了解ISL1失调是如何导致糖尿病病原的.
主要方法:
- 在小鼠内分泌前体中条件删除Isl1.
- 单细胞RNA测序 (scRNA-seq) 用于转录分析.
- 染色体分析 (H3K27ac和H3K27me3) 用于评估表观遗传特征.
- 长度单细胞分析ISl1缺乏的小岛屿.
主要成果:
- 失去ISL1会破坏小岛的表观遗传和转录格局.
- 缺少ISL1导致阿尔法细胞身份失败,三角形和马细胞丧失,以及功能受损的未成熟β细胞.
- 缺少Isl1的细胞表现出持续的祖先状状态,缺陷的β细胞成熟,以及与压力/糖尿病相关的途径的激活.
- 在ISL1缺乏的小鼠中观察到明显的性别特异性反应.
结论:
- ISL1对于保存内分泌细胞命运,促进血统承诺,并使终端分化成为可能至关重要.
- ISL1充当转录抑制剂,促进染色质重塑成熟内分泌细胞功能.
- 通过破坏小岛细胞的成熟和功能,ISL1失调会导致糖尿病,对疾病进展有潜在的性别特异性影响.
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