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

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          Summary

          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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          Highlights

          • •

            HNF4A is downregulated and predominantly mislocalized in the cytoplasm in MODY1

          • •

            Foregut markers, pancreatic and hepatic genes, were downregulated in MODY1-HPPs

          • •

            A reciprocal upregulation of hindgut HOX genes was observed in MODY1-HPPs

          • •

            Mutant HNF4A resulted in loss of transcriptional activation of target genes

          Abstract

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

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          Most cited references52

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          Generation of functional human pancreatic β cells in vitro.

          Felicia W Pagliuca, Jeffrey Millman, Mads Gürtler … (2014)
          The generation of insulin-producing pancreatic β cells from stem cells in vitro would provide an unprecedented cell source for drug discovery and cell transplantation therapy in diabetes. However, insulin-producing cells previously generated from human pluripotent stem cells (hPSC) lack many functional characteristics of bona fide β cells. Here, we report a scalable differentiation protocol that can generate hundreds of millions of glucose-responsive β cells from hPSC in vitro. These stem-cell-derived β cells (SC-β) express markers found in mature β cells, flux Ca(2+) in response to glucose, package insulin into secretory granules, and secrete quantities of insulin comparable to adult β cells in response to multiple sequential glucose challenges in vitro. Furthermore, these cells secrete human insulin into the serum of mice shortly after transplantation in a glucose-regulated manner, and transplantation of these cells ameliorates hyperglycemia in diabetic mice. Copyright © 2014 Elsevier Inc. All rights reserved.
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            Genome-wide association study in individuals of South Asian ancestry identifies six new type 2 diabetes susceptibility loci.

            Jaspal S Kooner, Danish Saleheen, Xueling Sim … (2011)
            We carried out a genome-wide association study of type-2 diabetes (T2D) in individuals of South Asian ancestry. Our discovery set included 5,561 individuals with T2D (cases) and 14,458 controls drawn from studies in London, Pakistan and Singapore. We identified 20 independent SNPs associated with T2D at P < 10(-4) for testing in a replication sample of 13,170 cases and 25,398 controls, also all of South Asian ancestry. In the combined analysis, we identified common genetic variants at six loci (GRB14, ST6GAL1, VPS26A, HMG20A, AP3S2 and HNF4A) newly associated with T2D (P = 4.1 × 10(-8) to P = 1.9 × 10(-11)). SNPs at GRB14 were also associated with insulin sensitivity (P = 5.0 × 10(-4)), and SNPs at ST6GAL1 and HNF4A were also associated with pancreatic beta-cell function (P = 0.02 and P = 0.001, respectively). Our findings provide additional insight into mechanisms underlying T2D and show the potential for new discovery from genetic association studies in South Asians, a population with increased susceptibility to T2D.
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              Mutations in the hepatocyte nuclear factor-4alpha gene in maturity-onset diabetes of the young (MODY1)

              Kazuya Yamagata, Hiroto Furuta, Naohisa Oda … (1996)
              The disease maturity-onset diabetes of the young (MODY) is a genetically heterogeneous monogenic form of non-insulin-dependent (type 2) diabetes mellitus (NIDDM), characterized by early onset, usually before 25 years of age and often in adolescence or childhood, and by autosomal dominant inheritance. It has been estimated that 2-5% of patients with NIDDM may have this form of diabetes mellitus. Clinical studies have shown that prediabetic MODY subjects have normal insulin sensitivity but suffer from a defect in glucose-stimulated insulin secretion, suggesting that pancreatic beta-cell dysfunction rather than insulin resistance is the primary defect in this disorder. Linkage studies have localized the genes that are mutated in MODY on human chromosomes 20 (MODY1), 7 (MODY2) and 12 (MODY3), with MODY2 and MODY3 being allelic with the genes encoding glucokinase, a key regulator of insulin secretion, and hepatocyte nuclear factor-1alpha (HNF-1alpha), a transcription factor involved in tissue-specific regulation of liver genes but also expressed in pancreatic islets, insulinoma cells and other tissues. Here we show that MODY1 is the gene encoding HNF-4alpha (gene symbol, TCF14), a member of the steroid/thyroid hormone receptor superfamily and an upstream regulator of HNF-1alpha expression.
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                Author and article information

                Contributors
                Adrian Kee Keong Teo
                Journal
                Journal ID (nlm-ta): iScience
                Journal ID (iso-abbrev): iScience
                Title: iScience
                Publisher: Elsevier
                ISSN (Electronic): 2589-0042
                Publication date PMC-release: 27 May 2019
                Publication date Collection: 28 June 2019
                Publication date (Electronic): 27 May 2019
                Volume: 16
                Pages: 192-205
                Affiliations
                [1 ]Stem Cells and Diabetes Laboratory, Institute of Molecular and Cell Biology, A*STAR, Singapore 138673, Singapore
                [2 ]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
                [7 ]KG Jebsen Center for Diabetes Research, Department of Clinical Science, Faculty of Medicine, University of Bergen, 5020 Bergen, Norway
                [8 ]Wellcome Trust Sanger Institute, Hinxton CB10 1SA, UK
                [9 ]Department of Biochemistry and Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117596, Singapore
                Author notes
                [∗ ]Corresponding author drainteo@ 123456gmail.com
                [10]

                These authors contributed equally

                [11]

                Lead Contact

                Article
                Publisher ID: S2589-0042(19)30169-5
                DOI: 10.1016/j.isci.2019.05.032
                PMC ID: 6562146
                PubMed ID: 31195238
                SO-VID: 6dace740-1983-4892-aac5-50aaeadffefa
                Copyright © © 2019 The Author(s)
                License:

                This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

                History
                Date received : 25 June 2018
                Date revision received : 20 November 2018
                Date accepted : 22 May 2019
                Categories
                Subject: Article

                Keywords: molecular mechanism of gene regulation,diabetology,stem cells research,developmental biology
                Data availability:
                Keywords: molecular mechanism of gene regulation, diabetology, stem cells research, developmental biology

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