HNF4A Haploinsufficiency in MODY1 Abrogates Liver and Pancreas Differentiation from Patient-Derived Induced Pluripotent Stem Cells
Year: 2019
Type: article
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.
Source: iScience
Institutions: Agency for Science, Technology and Research, Institute of Molecular and Cell Biology, Nanyang Technological University, Wellcome/MRC Cambridge Stem Cell Institute, University of Cambridge, Brigham and Women's Hospital, Joslin Diabetes Center, Harvard University, Harvard Stem Cell Institute, Haukeland University Hospital, University of Bergen, Wellcome Sanger Institute, Medical Research Council, National University of Singapore
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $3,000
Funders: U.S. Department of Commerce, Lee Foundation, Wellcome Trust, NIHR Biomedical Research Centre, Royal Marsden NHS Foundation Trust/Institute of Cancer Research, Duke-NUS Medical School, National Institute for Health and Care Research, University of Cambridge, Agency for Science, Technology and Research, Cambridge University Hospitals, Novo Nordisk, Diabetesforbundet, Novo Nordisk Fonden, National Institutes of Health, Medical Research Council, European Research Council, National Medical Research Council, Helse Vest Regionalt Helseføretak, Institute of Molecular and Cell Biology, National Institute of Diabetes and Digestive and Kidney Diseases
OpenAlex ID: W2946912605