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 and Matthias Hebrok ()
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Sapna Puri: University of California
Hasna Maachi: University of California
Gopika Nair: University of California
Holger A. Russ: University of California
Richard Chen: University of California
Pamela Pulimeno: University of California
Zachary Cutts: University of California
Vasilis Ntranos: University of California
Matthias Hebrok: University of California

Nature Communications, 2024, vol. 15, issue 1, 1-17

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-023-44384-8

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