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单细胞多原子分析揭示了由HNF1A驱动的糖尿病相关β细胞异质性

Chen Weng^1,2, Anniya Gu^1,3, Shanshan Zhang^1,2

¹Department of Genetics and Genome Sciences, School of Medicine, Case Western Reserve University, Cleveland, OH, 44106, USA.

Nature communications

|September 5, 2023

概括

二型糖尿病 (T2D) 涉及各种各样的胰腺β细胞差异. 这项研究揭示了T2Dβ细胞中的特定转录组和表观组变化,确定HNF1A是影响细胞功能和电流的关键因素.

科学领域:

内分泌学在内分泌学.
基因组学就是基因组学.
细胞生物学细胞生物学

背景情况:

胰腺β细胞表现出显著的功能和形态异质性.
鉴定β细胞中糖尿病相关的异质性对于理解II型糖尿病 (T2D) 发病过程至关重要.
现有的研究缺乏对T2D中人类小岛的综合多原子单细胞分析.

研究的目的:

在转录和表观基因层面上确定人类胰腺β细胞中与II型糖尿病 (T2D) 相关的异质性.
开发用于剖析捐赠者内和捐赠者间β细胞异质性的计算方法.
阐明特定基因 (如HNF1A) 在T2D病变发生过程中的作用.

主要方法:

整合单细胞RNA测序 (scRNA-seq),转化酶可访问的染色体测序 (scATAC-seq) 的单核测定和3D基因组造型.
开发计算方法来分析捐赠者内部和捐赠者之间的异质性.
对来自T2D和非糖尿病捐赠者的人类小岛的基因表达和染色质可访问性的分析.

主要成果:

在与T2D相关的β细胞中识别出明显的转录基因和表观基因异质特征.
肝细胞核因子1α (HNF1A) 被确定为捐赠者内β细胞异质性的关键调节者.
在T2Dβ细胞中观察到减少的HNF1A表达,与改变的Na+电流相关,并将FXYD2作为潜在的缓解因子.

结论:

单细胞多原子分析对于发现与疾病相关的细胞异质性是有价值的.
HNF1A在β细胞异质性中起着重要作用,并且在II型糖尿病中失调.
这些发现为T2D病原体提供了新的见解,突出了β细胞内的特定分子机制.

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