Biomedical Graduate Studies Program, University of California, San Diego, La Jolla, CA, USA.
Department of Pediatrics, Pediatric Diabetes Research Center, University of California, San Diego, La Jolla, CA, USA.
Nat Genet. 2021 Apr;53(4):455-466. doi: 10.1038/s41588-021-00823-0. Epub 2021 Apr 1.
Single-nucleus assay for transposase-accessible chromatin using sequencing (snATAC-seq) creates new opportunities to dissect cell type-specific mechanisms of complex diseases. Since pancreatic islets are central to type 2 diabetes (T2D), we profiled 15,298 islet cells by using combinatorial barcoding snATAC-seq and identified 12 clusters, including multiple alpha, beta and delta cell states. We cataloged 228,873 accessible chromatin sites and identified transcription factors underlying lineage- and state-specific regulation. We observed state-specific enrichment of fasting glucose and T2D genome-wide association studies for beta cells and enrichment for other endocrine cell types. At T2D signals localized to islet-accessible chromatin, we prioritized variants with predicted regulatory function and co-accessibility with target genes. A causal T2D variant rs231361 at the KCNQ1 locus had predicted effects on a beta cell enhancer co-accessible with INS and genome editing in embryonic stem cell-derived beta cells affected INS levels. Together our findings demonstrate the power of single-cell epigenomics for interpreting complex disease genetics.
利用测序进行单细胞核可及染色质分析 (snATAC-seq) 为解析复杂疾病的细胞类型特异性机制创造了新的机会。由于胰岛是 2 型糖尿病 (T2D) 的核心，我们通过组合条形码 snATAC-seq 对 15298 个胰岛细胞进行了分析，鉴定出 12 个簇，包括多个 alpha、beta 和 delta 细胞状态。我们对 228833 个可及染色质位点进行了编目，并鉴定了谱系和状态特异性调节的转录因子。我们观察到 beta 细胞中与空腹血糖和 T2D 全基因组关联研究相关的特定状态富集，以及其他内分泌细胞类型的富集。在 T2D 信号定位于胰岛可及染色质的情况下，我们优先考虑具有预测调节功能和与靶基因共可及性的变体。位于 KCNQ1 基因座的 T2D 风险变体 rs231361 对 INS 共可及的 beta 细胞增强子具有预测作用，并且在胚胎干细胞衍生的 beta 细胞中的基因编辑影响了 INS 水平。我们的研究结果共同证明了单细胞表观基因组学在解释复杂疾病遗传学方面的强大功能。
