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Walth-Hummel, A.A. ; Jouffe, C. ; Weber, P. ; Motzler, K. ; Geppert, J. ; Sterr, M. ; Gan, W.* ; Szczerbinska, I.* ; König, A.-C. ; Hauck, S.M. ; Terron Exposito, R. ; Hass, D, ; Wang, C. ; Dyar, K.A. ; Lyon, J.G.* ; Lickert, H. ; Ämmälä, C.* ; Herzig, S. ; Ashcroft, F.M.* ; Bakhti, M. ; MacDonald, P.E.* ; Rohm, M.

TBL1X/TBL1XR1 govern β-cell identity through a PAX6-containing gene regulatory network.

Nat. Commun. 17:3736 (2026)
Verlagsversion Forschungsdaten DOI PMC
Open Access Gold
Creative Commons Lizenzvertrag
A main mechanism of β-cell dysfunction in diabetes is loss of identity, controlled by transcription factors that induce identity gene expression and disallowed gene repression. How transcription factors facilitate simultaneous expression and repression is not fully understood, representing a knowledge gap in diabetes research. We identify the transcriptional co-factors transducin β-like 1 x-linked (TBL1X) and its homolog TBL1X-related (TBL1XR1, together TBL/R1) as crucial regulators of β-cell identity and determinants of diabetes development and progression. β-cell specific TBL/R1 knockout in mice leads to progressive hypoinsulinemia and hyperglycemia. scRNA-sequencing reveals loss of β-cells, emergence of polyhormonal cells, and reduced β-cell maturity upon TBL/R1 knockout. Interactome screens and chromatin immunoprecipitation show TBL/R1 directly regulate insulin promoter activity through a PAX6-HDAC3 gene regulatory network, evident also in human models. TBL/R1 associates with diabetes in humans, thus our study uncovers an additional regulatory layer maintaining β-cell identity crucial for diabetes development and progression.
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Schlagwörter Set Enrichment Analysis; Semantic Similarity; Expression; Transcription; Tbl1; Complex; Glucose; Pax6; Identification; Dysfunction
ISSN (print) / ISBN 2041-1723
e-ISSN 2041-1723
Zeitschrift Nature Communications
Quellenangaben Band: 17, Heft: 1, Seiten: , Artikelnummer: 3736 Supplement: ,
Verlag Springer
Verlagsort London
Begutachtungsstatus Peer reviewed
Institut(e) Institute of Diabetes and Cancer (IDC)
Translational Metabolic Oncology (IDC-TMO)
Institute of Diabetes and Regeneration Research (IDR)
CF Metabolomics & Proteomics (CF-MPC)
Förderungen Deutsche Forschungsgemeinschaft (German Research Foundation)