Department of Genetic Medicine and Development, University of Geneva Medical School, Geneva 1211, Switzerland.
Genome Res. 2013 Sep;23(9):1554-62. doi: 10.1101/gr.150706.112. Epub 2013 May 28.
Elucidating the pathophysiology and molecular attributes of common disorders as well as developing targeted and effective treatments hinges on the study of the relevant cell type and tissues. Pancreatic beta cells within the islets of Langerhans are centrally involved in the pathogenesis of both type 1 and type 2 diabetes. Describing the differentiated state of the human beta cell has been hampered so far by technical (low resolution microarrays) and biological limitations (whole islet preparations rather than isolated beta cells). We circumvent these by deep RNA sequencing of purified beta cells from 11 individuals, presenting here the first characterization of the human beta cell transcriptome. We perform the first comparison of gene expression profiles between beta cells, whole islets, and beta cell depleted islet preparations, revealing thus beta-cell-specific expression and splicing signatures. Further, we demonstrate that genes with consistent increased expression in beta cells have neuronal-like properties, a signal previously hypothesized. Finally, we find evidence for extensive allelic imbalance in expression and uncover genetic regulatory variants (eQTLs) active in beta cells. This first molecular blueprint of the human beta cell offers biological insight into its differentiated function, including expression of key genes associated with both major types of diabetes.
阐明常见疾病的病理生理学和分子特征，以及开发针对性和有效的治疗方法，都依赖于对相关细胞类型和组织的研究。胰岛中的胰岛β细胞在 1 型和 2 型糖尿病的发病机制中起着核心作用。到目前为止，描述人类β细胞的分化状态受到技术（低分辨率微阵列）和生物学限制（整个胰岛制剂而不是分离的β细胞）的阻碍。我们通过对 11 个人的纯化β细胞进行深度 RNA 测序来规避这些问题，在此首次对人类β细胞转录组进行了描述。我们首次比较了β细胞、整个胰岛和β细胞耗尽的胰岛制剂之间的基因表达谱，从而揭示了β细胞特异性表达和剪接特征。此外，我们还证明了在β细胞中一致表达增加的基因具有神经元样特性，这是之前假设的信号。最后，我们发现了表达中广泛的等位基因不平衡的证据，并发现了在β细胞中活跃的遗传调控变异（eQTLs）。人类β细胞的这第一个分子蓝图为其分化功能提供了生物学见解，包括与两种主要类型糖尿病相关的关键基因的表达。
