An HNF1α truncation associated with maturity-onset diabetes of the young impairs pancreatic progenitor differentiation by antagonizing HNF1β function

Ana Maria Cujba, Mario E. Alvarez-Fallas, Sergio Pedraza-Arevalo, Anna Laddach, Maggie H. Shepherd, Andrew T. Hattersley, Fiona M. Watt, Rocio Sancho*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

10 Citations (Scopus)

Abstract

The HNF1αp291fsinsC truncation is the most common mutation associated with maturity-onset diabetes of the young 3 (MODY3). Although shown to impair HNF1α signaling, the mechanism by which HNF1αp291fsinsC causes MODY3 is not fully understood. Here we use MODY3 patient and CRISPR/Cas9-engineered human induced pluripotent stem cells (hiPSCs) grown as 3D organoids to investigate how HNF1αp291fsinsC affects hiPSC differentiation during pancreatic development. HNF1αp291fsinsC hiPSCs shows reduced pancreatic progenitor and β cell differentiation. Mechanistically, HNF1αp291fsinsC interacts with HNF1β and inhibits its function, and disrupting this interaction partially rescues HNF1β-dependent transcription. HNF1β overexpression in the HNF1αp291fsinsC patient organoid line increases PDX1+ progenitors, while HNF1β overexpression in the HNF1αp291fsinsC patient iPSC line partially rescues β cell differentiation. Our study highlights the capability of pancreas progenitor-derived organoids to model disease in vitro. Additionally, it uncovers an HNF1β-mediated mechanism linked to HNF1α truncation that affects progenitor differentiation and could explain the clinical heterogeneity observed in MODY3 patients.

Original languageEnglish
Article number110425
JournalCell Reports
Volume38
Issue number9
DOIs
Publication statusPublished - 1 Mar 2022

Keywords

  • CRISPR/Cas9
  • diabetes
  • HNF1α
  • HNF1β
  • MODY3
  • organoid
  • p291fsinsC
  • pancreas
  • progenitor
  • β cell

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