Many studies have highlighted the role of dysregulated glucagon secretion in the etiology of hyperglycemia and diabetes. Accordingly, understanding the mechanisms underlying pancreatic islet α cell development and function has important implications for the discovery of new therapies for diabetes. In this study, comparative transcriptome analyses between embryonic mouse pancreas and adult mouse islets identified several pancreatic lncRNAs that lie in close proximity to essential pancreatic transcription factors, including the Pax6-associated lncRNA Paupar. We demonstrate that Paupar is enriched in glucagon-producing α cells where it promotes the alternative splicing of Pax6 to an isoform required for activation of essential α cell genes. Consistently, deletion of Paupar in mice resulted in dysregulation of PAX6 α cell target genes and corresponding α cell dysfunction, including blunted glucagon secretion. These findings illustrate a distinct mechanism by which a pancreatic lncRNA can coordinate glucose homeostasis by cell-specific regulation of a broadly expressed transcription factor.

中文翻译：

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长链非编码 RNA Paupar 调节 PAX6 调节活动以促进 α 细胞的发育和功能。

许多研究强调了胰高血糖素分泌失调在高血糖和糖尿病病因学中的作用。因此，了解胰岛 α 细胞发育和功能的潜在机制对于发现糖尿病新疗法具有重要意义。在这项研究中，胚胎小鼠胰腺和成年小鼠胰岛之间的比较转录组分析确定了几种胰腺 lncRNA，它们与必需的胰腺转录因子非常接近，包括 Pax6 相关的 lncRNA Paupar。我们证明 Paupar 富含产生胰高血糖素的 α 细胞，它促进 Pax6 选择性剪接为激活必需 α 细胞基因所需的同种型。始终如一，小鼠 Paupar 缺失导致 PAX6 α 细胞靶基因失调和相应的 α 细胞功能障碍，包括胰高血糖素分泌减弱。这些发现说明了一种独特的机制，通过该机制，胰腺 lncRNA 可以通过细胞特异性调节广泛表达的转录因子来协调葡萄糖稳态。