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iScience. 2019 Jun 28;16:192-205. doi: 10.1016/j.isci.2019.05.032. Epub 2019 May 27.

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

Author information

1
Stem Cells and Diabetes Laboratory, Institute of Molecular and Cell Biology, A*STAR, Singapore 138673, Singapore.
2
Stem Cells and Diabetes Laboratory, Institute of Molecular and Cell Biology, A*STAR, Singapore 138673, Singapore; School of Biological Sciences, Nanyang Technological University, Singapore 637551, Singapore.
3
Molecular Engineering Lab, A*STAR, Singapore 138673, Singapore.
4
Wellcome Trust-Medical Research Council Cambridge Stem Cell Institute, Anne McLaren Laboratory, Department of Surgery, University of Cambridge, Cambridge CB2 0SZ, UK.
5
Section of Islet Cell and Regenerative Biology, Joslin Diabetes Center, Harvard Stem Cell Institute, Department of Medicine, Brigham and Women's Hospital, and Harvard Medical School, Boston, MA 02215, USA.
6
Department of Pediatrics, Haukeland University Hospital, 5021 Bergen, Norway; KG Jebsen Center for Diabetes Research, Department of Clinical Science, Faculty of Medicine, University of Bergen, 5020 Bergen, Norway.
7
Wellcome Trust-Medical Research Council Cambridge Stem Cell Institute, Anne McLaren Laboratory, Department of Surgery, University of Cambridge, Cambridge CB2 0SZ, UK; Wellcome Trust Sanger Institute, Hinxton CB10 1SA, UK.
8
Stem Cells and Diabetes Laboratory, Institute of Molecular and Cell Biology, A*STAR, Singapore 138673, Singapore; School of Biological Sciences, Nanyang Technological University, Singapore 637551, Singapore; Department of Biochemistry and Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117596, Singapore. Electronic address: drainteo@gmail.com.

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.

KEYWORDS:

Developmental Biology; Diabetology; Molecular Mechanism of Gene Regulation; Stem Cells Research

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