The long noncoding RNA Paupar modulates PAX6 regulatory activities to promote alpha cell development and function

Many studies have highlighted the role of dysregulated glucagon secretion in the etiology of hyperglycemia and diabetes. Accordingly, understanding the mechanisms underlying pancreatic islet alpha 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 alpha cells where it promotes the alternative splicing of Pax6 to an isoform required for activation of essential alpha cell genes. Consistently, deletion of Paupar in mice resulted in dysregulation of PAX6 alpha cell target genes and corresponding alpha 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.多项研究均已证实，胰高血糖素分泌失调在高血糖症与糖尿病的发病机制中发挥关键作用。相应地，解析胰岛α细胞发育与功能的调控机制，对于发掘糖尿病新型治疗方案具有重要意义。本研究通过对小鼠胚胎胰腺与成年胰岛开展比较转录组分析，鉴定出若干定位于关键胰腺转录因子邻近区域的胰腺长链非编码RNA（long non-coding RNA，lncRNA），其中包括与Pax6相关的lncRNA Paupar。本研究证实，Paupar在分泌胰高血糖素的α细胞中富集表达，并可促进Pax6的可变剪接，使其产生可激活关键α细胞功能基因的剪接异构体。与之一致的是，在小鼠体内敲除Paupar会导致Pax6调控的α细胞靶基因表达失调，并引发相应的α细胞功能异常，包括胰高血糖素分泌减弱。本研究结果揭示了一种独特的调控机制：胰腺lncRNA可通过细胞特异性调控广泛表达的转录因子，进而协调机体葡萄糖稳态。