HNF4A Haploinsufficiency in MODY1 Abrogates Liver and Pancreas Differentiation from Patient-Derived Induced Pluripotent Stem Cells

HNF4A Haploinsufficiency in MODY1 Abrogates Liver and Pancreas Differentiation from Patient-Derived Induced Pluripotent Stem Cells
Title:
HNF4A Haploinsufficiency in MODY1 Abrogates Liver and Pancreas Differentiation from Patient-Derived Induced Pluripotent Stem Cells
Other Titles:
iScience
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Publication Date:
26 May 2019
Citation:
HNF4A Haploinsufficiency in MODY1 Abrogates Liver and Pancreas Differentiation from Patient-Derived Induced Pluripotent Stem Cells Ng, Natasha Hui Jin et al. iScience, Volume 16, 192 - 205
Abstract:
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.
License type:
http://creativecommons.org/licenses/by-nc-nd/4.0/
Funding Info:
The authors thank Andreas Alvin Purnomo Soetedjo and Chek Mei Bok for experimental assistance and also thank members of the Teo laboratory for the critical reading of this manuscript. N.H.J.N. is supported by the National Medical Research Council (NMRC) Open Fund-Young Individual Research Grant (OF-YIRG) OFYIRG18May. R.N.K. acknowledges support from National Institutes of Health Grant RO1 067536. H.R. is supported by the Bergen Forskningsstiftelse (BFS), the Western Norway Regional Health Authority, the Novo Nordisk Foundation, and Diabetesforbundet. L.V. is funded by the ERC advanced grant New- Chol, the Cambridge University Hospitals National Institute for Health Research Biomedical Research Centre and the core support grant from the Wellcome Trust and Medical Research Council to the Wellcome– Medical Research Council Cambridge Stem Cell Institute. A.K.K.T. is supported by the Institute of Molecular and Cell Biology (IMCB), A*STAR, A*STAR JCO Career Development Award (CDA) 15302FG148, NMRC OFYIRG16may014, A*STAR ETPL Gap Funding ETPL/18-GAP005-R20H, Lee Foundation Grant SHTX/LFG/002/2018, Skin Innovation Grant SIG18011, NMRC OF-LCG/DYNAMO, FY2019 Sing-Health Duke-NUS Surgery Academic Clinical Program Research Support Program Grant, and the Precision Medicine and Personalised Therapeutics Joint Research Grant 2019.
Description:
ISSN:
2589-0042
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