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

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  • Additional Information
    • Source:
      Publisher: Cell Press Country of Publication: United States NLM ID: 101573691 Publication Model: Print Cited Medium: Internet ISSN: 2211-1247 (Electronic) NLM ISO Abbreviation: Cell Rep Subsets: MEDLINE
    • Publication Information:
      Original Publication: [Cambridge, MA] : Cell Press, c 2012-
    • Subject Terms:
      Diabetes Mellitus* ; Induced Pluripotent Stem Cells*; Hepatocyte Nuclear Factor 1-alpha/*genetics; Cell Differentiation ; Diabetes Mellitus, Type 2 ; Humans ; Pancreas
    • Abstract:
      The HNF1α p291fsinsC 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 HNF1α p291fsinsC 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 HNF1α p291fsinsC affects hiPSC differentiation during pancreatic development. HNF1α p291fsinsC hiPSCs shows reduced pancreatic progenitor and β cell differentiation. Mechanistically, HNF1α p291fsinsC interacts with HNF1β and inhibits its function, and disrupting this interaction partially rescues HNF1β-dependent transcription. HNF1β overexpression in the HNF1α p291fsinsC patient organoid line increases PDX1 + progenitors, while HNF1β overexpression in the HNF1α p291fsinsC 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.
      Competing Interests: Declaration of interests The authors declare no competing interests.
      (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)
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    • Grant Information:
      207529/Z/17/Z United Kingdom WT_ Wellcome Trust; 108874/Z/15/Z United Kingdom WT_ Wellcome Trust; MR/T015470/1 United Kingdom MRC_ Medical Research Council; MR/S000011/1 United Kingdom MRC_ Medical Research Council; United Kingdom WT_ Wellcome Trust
    • Contributed Indexing:
      Keywords: CRISPR/Cas9; HNF1α; HNF1β; MODY3; diabetes; organoid; p291fsinsC; pancreas; progenitor; β cell
    • Accession Number:
      0 (HNF1A protein, human)
      0 (Hepatocyte Nuclear Factor 1-alpha)
    • Subject Terms:
      Mason-Type Diabetes; Maturity-Onset Diabetes of the Young, Type 3
    • Publication Date:
      Date Created: 20220302 Date Completed: 20220411 Latest Revision: 20220716
    • Publication Date:
      20231215
    • Accession Number:
      PMC8905088
    • Accession Number:
      10.1016/j.celrep.2022.110425
    • Accession Number:
      35235779