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Puri, S.* ; Maachi, H. ; Nair, G.* ; Russ, H.A.* ; Chen, R.* ; Pulimeno, P.* ; Cutts, Z.* ; Ntranos, V.* ; Hebrok, M.

Sox9 regulates alternative splicing and pancreatic beta cell function.

Nat. Commun. 15:588 (2024)
Verlagsversion Forschungsdaten DOI PMC
Open Access Gold
Creative Commons Lizenzvertrag
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.
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Schlagwörter Transcriptional Network; Progenitor Cells; Stem-cells; Endocrine; Expression; Insulin; Dedifferentiation; Inactivation; Pdx1; Differentiation
Sprache englisch
Veröffentlichungsjahr 2024
HGF-Berichtsjahr 2024
ISSN (print) / ISBN 2041-1723
e-ISSN 2041-1723
Zeitschrift Nature Communications
Quellenangaben Band: 15, Heft: 1, Seiten: , Artikelnummer: 588 Supplement: ,
Verlag Nature Publishing Group
Verlagsort London
Begutachtungsstatus Peer reviewed
Institut(e) Institute for Diabetes und Organoid Technology (IDOT)
POF Topic(s) 30201 - Metabolic Health
Forschungsfeld(er) Helmholtz Diabetes Center
PSP-Element(e) G-509600-001
Förderungen JDRF postdoctoral fellowship
Kraft Family Fellowship
UCSF Flow Cytometry Core
JDRF
DOI 10.1038/s41467-023-44384-8
WOS ID 001145563900008
Scopus ID 85182651286
PubMed ID 38238288
Erfassungsdatum 2024-01-22
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