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

Cell Rep. 2022 Mar 1;38(9):110425. doi: 10.1016/j.celrep.2022.110425.

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.

Keywords: CRISPR/Cas9; HNF1α; HNF1β; MODY3; diabetes; organoid; p291fsinsC; pancreas; progenitor; β cell.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Differentiation
  • Diabetes Mellitus*
  • Diabetes Mellitus, Type 2
  • Hepatocyte Nuclear Factor 1-alpha / genetics*
  • Humans
  • Induced Pluripotent Stem Cells*
  • Pancreas

Substances

  • HNF1A protein, human
  • Hepatocyte Nuclear Factor 1-alpha

Supplementary concepts

  • Mason-Type Diabetes
  • Maturity-Onset Diabetes of the Young, Type 3