美国哥伦比亚大学Lori Sussel研究组的研究显示，长非编码RNA Paupar通过调节PAX6的调节活性来促进α细胞的发育和功能。 2019年10月10日，国际学术期刊《细胞—代谢》在线发表了这一成果。

研究人员通过对小鼠胚胎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，这些胰腺lncRNA与必需的胰腺转录因子（包括Pax6相关的lncRNA Paupar）非常相似。研究证明了产升胰高血糖素的α细胞富含Paupar，并且促进Pax6的选择性剪切，Pax6的选择性剪切是激活必需α细胞基因所需的。与此同时，小鼠中Paupar的缺失导致PAX6α细胞靶基因的失调和相应的α细胞功能障碍，包括胰高血糖素的分泌减弱。

这些发现揭示了胰腺lncRNA可以通过调控广泛表达特异性转录因子的细胞来协调葡萄糖稳态的独特机制。

据悉，许多研究证实了胰高血糖素分泌失调在高血糖症和糖尿病中的作用。因此，了解胰岛α细胞发育和功能机制对于发现新的糖尿病治疗方法具有重要意义。

附：英文原文

Title: The Long Noncoding RNA Paupar Modulates PAX6 Regulatory Activities to Promote Alpha Cell Development and Function

Author: Ruth A. Singer, Luis Arnes, Yi Cui, Jiguang Wang, Yuqian Gao, Michelle A. Guney, Kristin E. Burnum-Johnson, Raul Rabadan, Charles Ansong, Galya Orr, Lori Sussel

Issue&Volume: 10 October 2019

Abstract: 

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.

DOI: 10.1016/j.cmet.2019.09.013

Source: https://www.cell.com/cell-metabolism/fulltext/S1550-4131(19)30516-9