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

Journal Article · Tue Dec 03 04:00:00 EST 2019 · Cell Metabolism

DOI:https://doi.org/10.1016/j.cmet.2019.09.013· OSTI ID:1577851

Singer, Ruth A. ^[1]; Arnes, Luis ^[2]; Cui, Yi ^[3]; Wang, Jiguang ^[1]; Gao, Yuqian ^[3]; Guney, Michelle ^[4]; Burnum-Johnson, Kristin E. ^[3]; Rabadan, Raul ^[5]; Ansong, Charles K. ^[3]; Orr, Galya ^[3]; Sussel, Lori ^[6]

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1. Columbia University
2. University of Copenhagen
3. BATTELLE (PACIFIC NW LAB)
4. Colorado University Medical Center
5. Columbia University Medical Center
6. University of Colorado

Many studies have highlighted the role of dysregulated glucagon secretion in the etiology of hyperglycemia and diabetes. Accordingly, understanding the mechanisms underlying pancreatic islet ? 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 ? cells where it promotes the alternative splicing of Pax6 to an isoform required for activation of essential ??cell genes. Consistently, deletion of Paupar in mice resulted in dysregulation of PAX6 ? cell target genes and corresponding ? 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.

• Research Organization: Pacific Northwest National Laboratory (PNNL), Richland, WA (United States)
• Sponsoring Organization: USDOE
• DOE Contract Number: AC05-76RL01830
• OSTI ID: 1577851
• Report Number(s): PNNL-SA-146887
• Journal Information: Cell Metabolism, Journal Name: Cell Metabolism Journal Issue: 6 Vol. 30
• Country of Publication: United States
• Language: English

Related Subjects

diabetes
pancreatic islets
glucagon
alpha cells
Paupar
lncRNAs
long noncoding RNAs
Pax6
acid mine drainage