小柯机器人

近日，美国加州大学圣地亚哥分校Kyle J. Gaulton、Joshua Chiou等研究人员合作通过遗传学和单细胞表观基因组学解析1型糖尿病的风险因素。2021年5月19日，国际知名学术期刊《自然》在线发表了这一成果。

研究人员结合了两种方法：520,580个1型糖尿病（T1D）样本的全基因组关联研究，以及131,554个细胞核的转座酶染色质可及性测序单核分析（snATAC–seq）。T1D的风险变体富含在T细胞和其他细胞类型（包括外分泌胰腺的腺泡和导管细胞）中活跃的cCRE。多个T1D信号的风险变异与外分泌特异性cCRE重叠，后者与具有外分泌特异性表达的基因相关。在CFTR基因座，T1D风险变异rs7795896映射到调节CFTR的导管特异性cCRE。风险等位基因降低了导管细胞中转录因子的结合，增强子的活性和CFTR的表达。这些发现支持外分泌胰腺在T1D发病机理中的作用，并强调了大规模的全基因组关联研究和单细胞表观基因组学对于了解复杂疾病细胞起源的作用。

据介绍，在复杂疾病的全基因组关联研究中已经确定的遗传风险变异主要是非编码性的。将这些风险变量转化为机制的见解需要详细的疾病相关细胞类型中基因调控的图谱。

附：英文原文

Title: Interpreting type 1 diabetes risk with genetics and single-cell epigenomics

Author: Joshua Chiou, Ryan J. Geusz, Mei-Lin Okino, Jee Yun Han, Michael Miller, Rebecca Melton, Elisha Beebe, Paola Benaglio, Serina Huang, Katha Korgaonkar, Sandra Heller, Alexander Kleger, Sebastian Preissl, David U. Gorkin, Maike Sander, Kyle J. Gaulton

Issue&Volume: 2021-05-19

Abstract: Genetic risk variants that have been identified in genome-wide association studies of complex diseases are primarily non-coding1. Translating these risk variants into mechanistic insights requires detailed maps of gene regulation in disease-relevant cell types2. Here we combined two approaches: a genome-wide association study of type 1 diabetes (T1D) using 520,580 samples, and the identification of candidate cis-regulatory elements (cCREs) in pancreas and peripheral blood mononuclear cells using single-nucleus assay for transposase-accessible chromatin with sequencing (snATAC–seq) of 131,554 nuclei. Risk variants for T1D were enriched in cCREs that were active in T cells and other cell types, including acinar and ductal cells of the exocrine pancreas. Risk variants at multiple T1D signals overlapped with exocrine-specific cCREs that were linked to genes with exocrine-specific expression. At the CFTR locus, the T1D risk variant rs7795896 mapped to a ductal-specific cCRE that regulated CFTR; the risk allele reduced transcription factor binding, enhancer activity and CFTR expression in ductal cells. These findings support a role for the exocrine pancreas in the pathogenesis of T1D and highlight the power of large-scale genome-wide association studies and single-cell epigenomics for understanding the cellular origins of complex disease.

DOI: 10.1038/s41586-021-03552-w

Source: https://www.nature.com/articles/s41586-021-03552-w

Nature：《自然》，创刊于1869年。隶属于施普林格·自然出版集团，最新IF：69.504
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