Single-Cell Heterogeneity Analysis and CRISPR Screen Identify Key β-Cell-Specific Disease Genes

Publication date: 12 March 2019Source: Cell Reports, Volume 26, Issue 11Author(s): Zhou Fang, Chen Weng, Haiyan Li, Ran Tao, Weihua Mai, Xiaoxiao Liu, Leina Lu, Sisi Lai, Qing Duan, Carlos Alvarez, Peter Arvan, Anthony Wynshaw-Boris, Yun Li, Yanxin Pei, Fulai Jin, Yan LiSummaryIdentification 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 β 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 β-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.Graphical Abstract
Source: Cell Reports - Category: Cytology Source Type: research