Department of Computational Medicine & Bioinformatics, University of Michigan, Ann Arbor, MI.
Department of Human Genetics, University of Michigan, Ann Arbor, MI.
Diabetes. 2021 Jul;70(7):1581-1591. doi: 10.2337/db20-1087. Epub 2021 Apr 13.
Identifying the tissue-specific molecular signatures of active regulatory elements is critical to understand gene regulatory mechanisms. Here, we identify transcription start sites (TSS) using cap analysis of gene expression (CAGE) across 57 human pancreatic islet samples. We identify 9,954 reproducible CAGE tag clusters (TCs), ∼20% of which are islet specific and occur mostly distal to known gene TSS. We integrated islet CAGE data with histone modification and chromatin accessibility profiles to identify epigenomic signatures of transcription initiation. Using a massively parallel reporter assay, we validated the transcriptional enhancer activity for 2,279 of 3,378 (∼68%) tested islet CAGE elements (5% false discovery rate). TCs within accessible enhancers show higher enrichment to overlap type 2 diabetes genome-wide association study (GWAS) signals than existing islet annotations, which emphasizes the utility of mapping CAGE profiles in disease-relevant tissue. This work provides a high-resolution map of transcriptional initiation in human pancreatic islets with utility for dissecting active enhancers at GWAS loci.
鉴定活跃调控元件的组织特异性分子特征对于理解基因调控机制至关重要。在这里，我们使用基因表达的帽分析（CAGE）在 57 个人胰岛样本中鉴定转录起始位点（TSS）。我们鉴定了 9954 个可重复的 CAGE 标签簇（TC），其中约 20%是胰岛特异性的，主要发生在已知基因 TSS 的远端。我们将胰岛 CAGE 数据与组蛋白修饰和染色质可及性图谱相结合，以鉴定转录起始的表观基因组特征。使用大规模平行报告基因检测，我们验证了 3378 个（约 68%）测试胰岛 CAGE 元件中的 2279 个（5%的假发现率）的转录增强子活性。可及增强子内的 TC 与 2 型糖尿病全基因组关联研究（GWAS）信号的重叠富集程度高于现有胰岛注释，这强调了在疾病相关组织中绘制 CAGE 图谱的实用性。这项工作提供了人类胰岛中转录起始的高分辨率图谱，可用于剖析 GWAS 位点的活跃增强子。
