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该位点的多个基因变异影响局部超级增强子活性，并影响胰腺β细胞的存活和功能。

Multiple genetic variants at the locus affect local super-enhancer activity and influence pancreatic β-cell survival and function.

作者信息

Hu Ming, Kim Innah, Morán Ignasi, Peng Weicong, Sun Orien, Bonnefond Amélie, Khamis Amna, Bonas-Guarch Silvia, Froguel Philippe, Rutter Guy A

机构信息

Section of Cell Biology and Functional Genomics, Division of Diabetes, Endocrinology and Metabolism, Department of Metabolism, Digestion and Reproduction, Faculty of Medicine, Imperial College London, Du Cane Road, London W12 0NN, UK.

Life Sciences Department, Barcelona Supercomputing Center (BSC-CNS), 08034 Barcelona, Spain.

出版信息

bioRxiv. 2023 Oct 11:2023.07.13.548906. doi: 10.1101/2023.07.13.548906.

DOI:10.1101/2023.07.13.548906
PMID:37502937
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10369998/
Abstract

Variants at the locus are associated with type 2 diabetes (T2D) risk. The lead variant, rs13266634, encodes an amino acid change, Arg325Trp (R325W), at the C-terminus of the secretory granule-enriched zinc transporter, ZnT8. Although this protein-coding variant was previously thought to be the sole driver of T2D risk at this locus, recent studies have provided evidence for lowered expression of mRNA in protective allele carriers. In the present study, combined allele-specific expression (cASE) analysis in human islets revealed multiple variants that influence expression. Epigenomic mapping identified an islet-selective enhancer cluster at the locus, hosting multiple T2D risk and cASE associations, which is spatially associated with the promoter and additional neighbouring genes. Deletions of variant-bearing enhancer regions using CRISPR-Cas9 in human-derived EndoC-βH3 cells lowered the expression of and several neighbouring genes, and improved insulin secretion. Whilst down-regulation of had no effect on beta cell survival, loss of , markedly reduced cell viability. Although eQTL or cASE analyses in human islets did not support the association between these additional genes and diabetes risk, the transcriptional regulator JQ1 lowered the expression of multiple genes at the locus and enhanced stimulated insulin secretion.

摘要

该位点的变异与2型糖尿病（T2D）风险相关。主要变异体rs13266634编码分泌颗粒富集锌转运蛋白ZnT8 C末端的氨基酸变化，即Arg325Trp（R325W）。尽管这种蛋白质编码变异体以前被认为是该位点T2D风险的唯一驱动因素，但最近的研究提供了证据，表明在携带保护性等位基因的个体中，该基因的mRNA表达降低。在本研究中，对人类胰岛进行的联合等位基因特异性表达（cASE）分析揭示了多个影响该基因表达的变异体。表观基因组图谱在该位点鉴定出一个胰岛选择性增强子簇，该簇包含多个T2D风险和cASE关联，并且在空间上与该基因的启动子和其他邻近基因相关。在人源EndoC-βH3细胞中使用CRISPR-Cas9删除携带变异的增强子区域，降低了该基因及几个邻近基因的表达，并改善了胰岛素分泌。虽然该基因的下调对β细胞存活没有影响，但其他基因的缺失显著降低了细胞活力。尽管在人类胰岛中进行的eQTL或cASE分析不支持这些额外基因与糖尿病风险之间的关联，但转录调节因子JQ1降低了该位点多个基因的表达，并增强了刺激后的胰岛素分泌。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b3ba/10584242/99a1cbd09ffa/nihpp-2023.07.13.548906v2-f0008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b3ba/10584242/b96a96dcc075/nihpp-2023.07.13.548906v2-f0001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b3ba/10584242/4ab5acbf0e5c/nihpp-2023.07.13.548906v2-f0002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b3ba/10584242/04f320e6b008/nihpp-2023.07.13.548906v2-f0003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b3ba/10584242/2fdc81597631/nihpp-2023.07.13.548906v2-f0004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b3ba/10584242/296795384522/nihpp-2023.07.13.548906v2-f0005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b3ba/10584242/3f031d3266ca/nihpp-2023.07.13.548906v2-f0006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b3ba/10584242/047c576c1c9a/nihpp-2023.07.13.548906v2-f0007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b3ba/10584242/99a1cbd09ffa/nihpp-2023.07.13.548906v2-f0008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b3ba/10584242/b96a96dcc075/nihpp-2023.07.13.548906v2-f0001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b3ba/10584242/4ab5acbf0e5c/nihpp-2023.07.13.548906v2-f0002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b3ba/10584242/04f320e6b008/nihpp-2023.07.13.548906v2-f0003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b3ba/10584242/2fdc81597631/nihpp-2023.07.13.548906v2-f0004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b3ba/10584242/296795384522/nihpp-2023.07.13.548906v2-f0005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b3ba/10584242/3f031d3266ca/nihpp-2023.07.13.548906v2-f0006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b3ba/10584242/047c576c1c9a/nihpp-2023.07.13.548906v2-f0007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b3ba/10584242/99a1cbd09ffa/nihpp-2023.07.13.548906v2-f0008.jpg

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The Type 2 Diabetes Knowledge Portal: An open access genetic resource dedicated to type 2 diabetes and related traits.2 型糖尿病知识库：一个开放获取的遗传资源库，专门用于 2 型糖尿病和相关特征。
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Genetic regulation of RNA splicing in human pancreatic islets.人类胰岛中 RNA 剪接的遗传调控。
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