Sox9 regulates alternative splicing and pancreatic beta cell function

Sapna Puri, Hasna Maachi, Gopika Nair, Holger A. Russ, Richard Chen, Pamela Pulimeno, Zachary Cutts, Vasilis Ntranos, Matthias Hebrok

Research output: Contribution to journalArticlepeer-review

Abstract

Despite significant research, mechanisms underlying the failure of islet beta cells that result in type 2 diabetes (T2D) are still under investigation. Here, we report that Sox9, a transcriptional regulator of pancreas development, also functions in mature beta cells. Our results show that Sox9-depleted rodent beta cells have defective insulin secretion, and aging animals develop glucose intolerance, mimicking the progressive degeneration observed in T2D. Using genome editing in human stem cells, we show that beta cells lacking SOX9 have stunted first-phase insulin secretion. In human and rodent cells, loss of Sox9 disrupts alternative splicing and triggers accumulation of non-functional isoforms of genes with key roles in beta cell function. Sox9 depletion reduces expression of protein-coding splice variants of the serine-rich splicing factor arginine SRSF5, a major splicing enhancer that regulates alternative splicing. Our data highlight the role of SOX9 as a regulator of alternative splicing in mature beta cell function.

Original languageEnglish
Article number588
JournalNature Communications
Volume15
Issue number1
DOIs
StatePublished - Dec 2024

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