An HNF1α truncation associated with maturity-onset diabetes of the young impairs pancreatic progenitor differentiation by antagonizing HNF1β function.
An HNF1α truncation associated with maturity-onset diabetes of the young impairs pancreatic progenitor differentiation by antagonizing HNF1β function.
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DOI：
10.1016/j.celrep.2022.110425
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发表时间：
2022-03-01
期刊：
影响因子：
8.8
通讯作者：
Sancho R
中科院分区：
文献类型：
--
作者：
Cujba AM;Alvarez-Fallas ME;Pedraza-Arevalo S;Laddach A;Shepherd MH;Hattersley AT;Watt FM;Sancho R
HNF 1 α p291 fsinsC截短是与年轻人3型成熟型糖尿病（MODY 3）相关的最常见突变。虽然HNF 1 α p291 fsinsC可削弱HNF 1 α信号传导，但其导致MODY 3的机制尚不完全清楚。在这里，我们使用MODY 3患者和CRISPR/Cas9工程改造的人诱导多能干细胞（hiPSC）作为3D类器官生长，以研究HNF 1 α p291 fsinsC如何影响胰腺发育期间的hiPSC分化。HNF 1 α p291 fsinsC hiPSC显示胰腺祖细胞和β细胞分化减少。HNF 1 α p291 fsinsC与HNF 1 β相互作用并抑制其功能，破坏这种相互作用可部分挽救HNF 1 β依赖性转录。HNF 1 α p291 fsinsC患者类器官系中HNF 1 β过表达增加了PDX 1+祖细胞，而HNF 1 α p291 fsinsC患者iPSC系中HNF 1 β过表达部分挽救了β细胞分化。我们的研究强调了胰腺祖细胞衍生的类器官在体外模拟疾病的能力。此外，它揭示了与影响祖细胞分化的HNF 1 α截短相关的HNF 1 β介导的机制，并可以解释在MODY 3患者中观察到的临床异质性。MODY 3患者和CRISPR/Cas9 HNF 1 α p291 fsinsC突变的iPSC系产生突变iPSC显示胰腺祖细胞和β细胞分化缺陷突变截短的HNF 1 α蛋白结合野生型HNF 1 β蛋白以阻碍其功能HNF 1 β在MODY 3 iPSC系中的过表达部分挽救β细胞分化Cujba et al.使用人MODY 3患者和CRISPR/Cas9编辑的iPSC系，以显示HNF 1 α p291 fsinsC突变导致突变截短的HNF 1 α蛋白的表达，该突变截短的HNF 1 α蛋白与野生型HNF 1 β蛋白相互作用并抑制其功能，损害胰腺祖细胞和β细胞分化。
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. MODY3 patient and CRISPR/Cas9 HNF1αp291fsinsC mutated iPSC lines are generated Mutant iPSCs show deficient pancreatic progenitor and β cell differentiation Mutant truncated HNF1α protein binds wild-type HNF1β protein to hinder its function HNF1β overexpression in MODY3 iPSC line partially rescues β cell differentiation Cujba et al. use human MODY3 patient and CRISPR/Cas9 edited iPSC lines to show that the HNF1αp291fsinsC mutation results in the expression of a mutant truncated HNF1α protein that interacts with wild-type HNF1β protein and inhibits its function, impairing pancreatic progenitor and β cell differentiation.
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