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

Alina A Walth-Hummel1,2,3, Celine Jouffe1,3, Peter Weber1,2

  • 1Institute for Diabetes and Cancer (IDC), Helmholtz Diabetes Center, Helmholtz Center Munich, Neuherberg, Germany.

Nature Communications
|April 22, 2026
PubMed

Insights

Transducin β-like 1 (TBL1X) and TBL1X-related (TBL1XR1) are crucial for maintaining pancreatic beta-cell identity. Loss of these transcriptional co-factors in mice causes diabetes, highlighting their role in disease progression.

Area of Science:

  • Endocrinology
  • Molecular Biology
  • Genetics

Background:

  • Pancreatic beta-cell dysfunction, characterized by loss of identity, is a key mechanism in diabetes.
  • Transcription factors regulate beta-cell identity by controlling gene expression, but the mechanisms of simultaneous gene expression and repression are not fully understood.

Purpose of the Study:

  • To identify novel regulators of beta-cell identity and their role in diabetes development.
  • To investigate the function of transducin β-like 1 x-linked (TBL1X) and its homolog TBL1X-related (TBL1XR1) in maintaining beta-cell function.

Main Methods:

  • Generated beta-cell specific TBL/R1 knockout mice.
  • Performed scRNA-sequencing to analyze beta-cell populations.
  • Utilized interactome screens and chromatin immunoprecipitation assays.
  • Examined TBL/R1 association with diabetes in human cohorts.

Main Results:

  • Beta-cell specific TBL/R1 knockout mice exhibited progressive hypoinsulinemia and hyperglycemia.
  • scRNA-sequencing revealed beta-cell loss, polyhormonal cell emergence, and reduced beta-cell maturity in knockout mice.
  • TBL/R1 directly regulates insulin promoter activity via a PAX6-HDAC3 gene regulatory network, confirmed in human models.

Conclusions:

  • TBL/R1 are critical regulators of beta-cell identity and crucial determinants of diabetes development and progression.
  • Uncovered a novel regulatory layer involving TBL/R1 in maintaining beta-cell identity, essential for preventing diabetes.
  • Findings suggest TBL/R1 as potential therapeutic targets for diabetes treatment.

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