近年来对非编码RNA的深入研究解释了多种生物学过程中的机制，然而关于长非编码RNA在人类胰腺发育中的功能及调节机制的研究还很少。前期研究结果发现长非编码RNA DEANR1通过调节FOXA2表达参与早期胚层分化调控。本课题组最近的数据显示，DEANR1在胰腺发育阶段高表达，其上游转录调控区存在着一个和高血糖症状高度关联的SNP rs6048205。该SNP可以调控DEANR1表达，且不同的SNP基因亚型可以导致不同的胰腺分化效率。由此可推测rs6048205-DEANR1对胰腺发育有重要作用。本项目拟利用人多能干细胞胰腺定向诱导分化体系，研究DEANR1及位于其调控区的rs6048205在胰腺分化中的功能及作用机理，在进一步揭示DEANR1的功能及机制的基础上，解释一个血糖异常相关的SNP位点的可能致病机理，为后续研究提供一个胰腺发育异常及糖尿病易感的细胞研究模型。

The recent progress in noncoding RNA research in last decades provides mechanistic insights into various biological processes, however, the function of long noncoding RNA in human pancreas development is still largely unknown. We have characterized the lncRNA DEANR1 (Definitive Endoderm-Associated long Noncoding RNA 1), and demonstrated DEANR1 plays an important role in early endoderm development through regulating the expression of FOXA2. Our recent results indicate DEANR1 is also highly expressed during pancreatic specification; more interestingly, the SNP rs6048205, significantly associated with hyperglycemia trait, is located in the upstream of transcriptional start site of DEANR1 (-321nt) and able to transcriptionally regulate the expression of DEANR1. More importantly, human embryonic stem cell carrying different SNP allele exhibits differential pancreatic differentiation efficiency. Taken together, we hypothesize that rs6048205-DEANR1 probably plays a crucial role in human pancreatic development. Herein, we are aiming in this proposal to utilize the platform of directed pancreatic differentiation from human pluripotent stem cells to dissect the roles of long noncoding RNA DEANR1 and the upstream hyperglycemia-associated SNP rs6048205 in pancreas differentiation in detail, with the hope of extending the biological function of DEANR1, exploring the pathological mechanism of the hyperglycemia-associated SNP, and also providing a cell model to study diabetes due to pancreas development dysregulation.