小柯机器人

美国国立卫生研究院Francis S. Collins等研究人员合作，利用等基因人类胚胎干细胞衍生的β样细胞对20个2型糖尿病相关基因进行功能检测。2023年10月18日，国际知名学术期刊《细胞—代谢》在线发表了这一成果。

研究人员设计了20个与2型糖尿病（T2D）风险相关基因的等基因敲除人类胚胎干细胞系。研究人员揭示了每个基因敲除对β细胞分化、功能和存活的影响。研究人员生成了每个基因敲除品系β细胞的基因表达和染色质可及性图谱。通过分析与HNF4A依赖性ATAC峰重叠的T2D关联信号，研究人员发现FAIM2 T2D关联信号处可能存在一个因果变异。此外，整合关联分析还发现了与胰岛素分泌相关的四个基因（CP、RNASE1、PCSK1N和GSTA2），以及与β细胞对脂肪毒性的敏感性相关的两个基因（TAGLN3 和 DHRS2）。

最后，研究人员利用深度ATAC-seq读数覆盖率评估了亲本系杂合变异的等位基因特异性不平衡，并在23个T2D关联信号中的每个信号中发现了一个可能的功能性变异。

据悉，遗传研究发现了许多与T2D相关的基因位点，但许多基因位点的功能作用仍有待探索。

附：英文原文

Title: Functional interrogation of twenty type 2 diabetes-associated genes using isogenic human embryonic stem cell-derived β-like cells

Author: Dongxiang Xue, Narisu Narisu, D. Leland Taylor, Meili Zhang, Caleb Grenko, Henry J. Taylor, Tingfen Yan, Xuming Tang, Neelam Sinha, Jiajun Zhu, J. Jeya Vandana, Angie Chi Nok Chong, Angela Lee, Erin C. Mansell, Amy J. Swift, Michael R. Erdos, Aaron Zhong, Lori L. Bonnycastle, Ting Zhou, Shuibing Chen, Francis S. Collins

Issue&Volume: 2023-10-18

Abstract: Genetic studies have identified numerous loci associated with type 2 diabetes (T2D), but the functional roles of many loci remain unexplored. Here, we engineered isogenic knockout human embryonic stem cell lines for 20 genes associated with T2D risk. We examined the impacts of each knockout on β cell differentiation, functions, and survival. We generated gene expression and chromatin accessibility profiles on β cells derived from each knockout line. Analyses of T2D-association signals overlapping HNF4A-dependent ATAC peaks identified a likely causal variant at the FAIM2 T2D-association signal. Additionally, the integrative association analyses identified four genes (CP, RNASE1, PCSK1N, and GSTA2) associated with insulin production, and two genes (TAGLN3 and DHRS2) associated with β cell sensitivity to lipotoxicity. Finally, we leveraged deep ATAC-seq read coverage to assess allele-specific imbalance at variants heterozygous in the parental line and identified a single likely functional variant at each of 23 T2D-association signals.

DOI: 10.1016/j.cmet.2023.09.013

Source: https://www.cell.com/cell-metabolism/fulltext/S1550-4131(23)00369-8

Cell Metabolism：《细胞—代谢》，创刊于2005年。隶属于细胞出版社，最新IF：31.373
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