Single-Cell Heterogeneity Analysis and CRISPR Screen Identify Key β-Cell-Specific Disease Genes
Single-Cell Heterogeneity Analysis and CRISPR Screen Identify Key β-Cell-Specific Disease Genes
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DOI：
10.1016/j.celrep.2019.02.043
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发表时间：
2019-03-12
期刊：
影响因子：
8.8
通讯作者：
Li, Yan
中科院分区：
文献类型：
--
作者：
Fang, Zhou;Weng, Chen;Li, Yan
人类疾病特征基因的识别通常需要来自许多捐赠者的样本才能达到统计学意义。在这里，我们表明，单细胞异质性分析可以通过显著提高测试灵敏度来克服这一障碍。我们分析了来自9个捐赠者的39,905个单个胰岛细胞的转录组，观察到与肥胖或2型糖尿病(T2D)相关的独特的β细胞异质性轨迹。因此，我们开发了RePACT，这是一种敏感的单细胞分析算法，可以识别肥胖和T2D的共同和特定签名基因。我们将β细胞特异性基因和疾病特征基因映射到从全基因组CRISPR筛查中确定的胰岛素调节网络。我们的综合分析发现了先前未知的粘附素负载复合体和NuA4/Tip60组蛋白乙酰转移酶复合体在调节胰岛素转录和释放中的作用。我们的研究证明了结合单细胞异质性分析和功能基因组学来剖析复杂疾病的病因学的能力。
Identification of human disease signature genes typically requires samples from many donors to achieve statistical significance. Here, we show that single-cell heterogeneity analysis may overcome this hurdle by significantly improving the test sensitivity. We analyzed the transcriptome of 39,905 single islets cells from 9 donors and observed distinct beta cell heterogeneity trajectories associated with obesity or type 2 diabetes (T2D). We therefore developed RePACT, a sensitive single-cell analysis algorithm to identify both common and specific signature genes for obesity and T2D. We mapped both beta-cell-specific genes and disease signature genes to the insulin regulatory network identified from a genome-wide CRISPR screen. Our integrative analysis discovered the previously unrecognized roles of the cohesin loading complex and the NuA4/Tip60 histone acetyltransferase complex in regulating insulin transcription and release. Our study demonstrated the power of combining single-cell heterogeneity analysis and functional genomics to dissect the etiology of complex diseases.