A genome-wide CRISPR screen identifies CALCOCO2 as a regulator of beta cell function influencing type 2 diabetes risk.
A genome-wide CRISPR screen identifies CALCOCO2 as a regulator of beta cell function influencing type 2 diabetes risk.
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DOI：
10.1038/s41588-022-01261-2
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发表时间：
2023-01
期刊：
影响因子：
30.8
通讯作者：
Gloyn, Anna L.
中科院分区：
文献类型：
--
作者：
Rottner, Antje K.;Ye, Yingying;Navarro-Guerrero, Elena;Rajesh, Varsha;Pollner, Alina;Bevacqua, Romina J.;Yang, Jing;Spigelman, Aliya F.;Baronio, Roberta;Bautista, Austin;Thomsen, Soren K.;Lyon, James;Nawaz, Sameena;Smith, Nancy;Wesolowska-Andersen, Agata;Fox, Jocelyn E. Manning;Sun, Han;Kim, Seung K.;Ebner, Daniel;MacDonald, Patrick E.;Gloyn, Anna L.
识别基因和过程介导的复杂疾病的遗传关联信号是一个重大挑战。由于2型糖尿病（T2 D）的许多遗传信号通过胰岛细胞功能障碍发挥作用，我们在人类胰腺β细胞系中进行了全基因组合并CRISPR功能丧失筛选。我们评估了胰岛素含量的调节作为β细胞功能的疾病相关读数，并确定了580个影响这种表型的基因。与遗传和基因组数据的整合为20个候选T2 D效应转录本提供了实验支持，包括自噬受体CALCOCO 2。CALCOCO 2的丢失与线粒体变形、含胰岛素原的不成熟颗粒减少和晚期自噬抑制后自噬体的积累有关。在CALCOCO 2基因座处的T2 D相关变体的携带者进一步显示改变的胰岛素分泌。我们的研究强调了细胞筛选如何增强现有的多组学努力，以支持对机制的理解，并为全基因组关联研究位点的因果效应提供证据。在人类EndoC-βH1胰腺β细胞系中进行的全基因组CRISPR敲除筛选鉴定了580种细胞内胰岛素含量的调节因子。CALCOCO 2的缺失扰乱了胰腺β细胞中胰岛素颗粒的稳态。
Identification of the genes and processes mediating genetic association signals for complex diseases represents a major challenge. As many of the genetic signals for type 2 diabetes (T2D) exert their effects through pancreatic islet-cell dysfunction, we performed a genome-wide pooled CRISPR loss-of-function screen in a human pancreatic beta cell line. We assessed the regulation of insulin content as a disease-relevant readout of beta cell function and identified 580 genes influencing this phenotype. Integration with genetic and genomic data provided experimental support for 20 candidate T2D effector transcripts including the autophagy receptor CALCOCO2. Loss of CALCOCO2 was associated with distorted mitochondria, less proinsulin-containing immature granules and accumulation of autophagosomes upon inhibition of late-stage autophagy. Carriers of T2D-associated variants at the CALCOCO2 locus further displayed altered insulin secretion. Our study highlights how cellular screens can augment existing multi-omic efforts to support mechanistic understanding and provide evidence for causal effects at genome-wide association studies loci. A genome-wide CRISPR knockout screen in the human EndoC-βH1 pancreatic beta cell line identifies 580 regulators of intracellular insulin content. Loss of CALCOCO2 perturbs insulin granule homeostasis in pancreatic beta cells.
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影响因子：
7.7
作者：
Fiaschi-Taesch NM;Kleinberger JW;Salim FG;Troxell R;Wills R;Tanwir M;Casinelli G;Cox AE;Takane KK;Scott DK;Stewart AF
通讯作者：
Stewart AF
影响因子：
16.6
作者：
Greenwald, William W.;Chiou, Joshua;Gaulton, Kyle J.
通讯作者：
Gaulton, Kyle J.
人类胰岛中的开放染色质图。
影响因子：
30.8
作者：
Gaulton, Kyle J.;Nammo, Takao;Pasquali, Lorenzo;Simon, Jeremy M.;Giresi, Paul G.;Fogarty, Marie P.;Panhuis, Tami M.;Mieczkowski, Piotr;Secchi, Antonio;Bosco, Domenico;Berney, Thierry;Montanya, Eduard;Mohlke, Karen L.;Lieb, Jason D.;Ferrer, Jorge
通讯作者：
Ferrer, Jorge
影响因子：
16
作者：
Heo JM;Ordureau A;Paulo JA;Rinehart J;Harper JW
通讯作者：
Harper JW
影响因子：
5.6
作者：
Fahie K;Zachara NE
通讯作者：
Zachara NE