HNF4A Haploinsufficiency in MODY1 Abrogates Liver and Pancreas Differentiation from Patient-Derived Induced Pluripotent Stem Cells
Open accessAbstract
Maturity-onset diabetes of the young 1 (MODY1) is a monogenic diabetes condition caused by heterozygous HNF4A mutations. We investigate how HNF4A haploinsufficiency from a MODY1/HNF4A mutation influences the development of foregut-derived liver and pancreatic cells through differentiation of human induced pluripotent stem cells from a MODY1 family down the foregut lineage. In MODY1-derived hepatopancreatic progenitors, which expressed reduced HNF4A levels and mislocalized HNF4A, foregut genes were downregulated, whereas hindgut-specifying HOX genes were upregulated. MODY1-derived hepatocyte-like cells were found to exhibit altered morphology. Hepatic and β cell gene signatures were also perturbed in MODY1-derived hepatocyte-like and β-like cells, respectively. As mutant HNF4A (p.Ile271fs) did not undergo complete nonsense-mediated decay or exert dominant negativity, HNF4A-mediated loss of function is likely due to impaired transcriptional activation of target genes. Our results suggest that in MODY1, liver and pancreas development is perturbed early on, contributing to altered hepatic proteins and β cell defects in patients.
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Expression of HNF1A, HNF4A, and FOXA2 typically peaks during the early progenitor stage and decreases toward the final hepatocyte-like cell stage.
“This finding is consistent with other reports that these genes’ expression typically peaks during early progenitor stage and decreases towards the final hepatocyte-like cells stage24–26.”
From Temporal proteomic profiling of iPSC-derived human liver organoids reveals optimal maturation for drug metabolism and toxicology (2026) · cites this paper as [25]
The Results section ('MODY1-Mediated Loss of HNF4A Transcriptional Function Affects Subsequent Hepatic and Pancreatic Development Signatures'; page unavailable) reports that HNF4A expression peaked on day 8 of differentiation into hepatocyte-like cells, before other hepatic genes peaked on days 16 or 24. Our copy does not establish the same early peak and subsequent decline for HNF1A or FOXA2, so it supports only the HNF4A part of the claim. (LLM, conf=0.87)
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- Authors
- Ng, N. H. J., Jasmen, J. B., Lim, C. S., Lau, H. H., Krishnan, V. G., Kadiwala, J., Kulkarni, R. N., Ræder, H., Vallier, L., Hoon, S., & Teo, A. K. K.
- Affiliations
- Agency for Science, Technology and Research (SG)
- Wellcome/MRC Cambridge Stem Cell Institute (GB)
- Brigham and Women's Hospital (US)
- Haukeland University Hospital (NO)
- Corresponding author
- Teo, Adrian Kee Keong
- ORCID
- Venue
- iScience
- Publisher
- Elsevier BV
- Published
- 2019-06
- Volume
- 16
- Pages
- 192-205
- ISSN
- 2589-0042 (ISSN-L)
- PMC
- PMC6562146
- OpenAlex
- W2946912605
- Cited by
- 54
- References
- 60
- Citations by year
- 2026: 6 · 2025: 5 · 2024: 8 · 2023: 8 · 2022: 7 · 2021: 10 · 2020: 5 · 2019: 4 · 2017: 1
- FWCI
- 2.15
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- iScience (publishedVersion, cc-by-nc-nd)
- Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Apollo (University of Cambridge) (submittedVersion, cc-by-nc-nd)
- National University of Singapore (submittedVersion, cc-by-nc-nd)
- NORA - Norwegian Open Research Archives (submittedVersion, cc-by-nc-nd)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- DR-NTU (Nanyang Technological University) (submittedVersion, cc-by-nc-nd)
- Apollo
- Funders
- Institute of Molecular and Cell Biology
- Medical Research Council
- Novo Nordisk Fonden
- European Research Council
- Agency for Science, Technology and Research (15302FG148)
- National Institutes of Health (RO1 067536)
- National Medical Research Council
- Helse Vest Regionalt Helseføretak
- Wellcome Trust
- Lee Foundation (SHTX/LFG/002/2018, SIG18011)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Pluripotent Stem Cells Research
- Health Sciences › Medicine › Surgery › Pancreatic function and diabetes
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Diabetes and associated disorders
- Keywords
- HNF4α, MODY1, haploinsufficiency, monogenic diabetes, induced pluripotent stem cells, hepatocyte differentiation, pancreatic beta cell differentiation, foregut development, nonsense-mediated mRNA decay, dominant negative effect, transcriptional activation, Hox genes, liver development
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