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Cell Stem Cell. 2019 Aug 1;25(2):273-289.e5. doi: 10.1016/j.stem.2019.07.007.

Modeling Monogenic Diabetes using Human ESCs Reveals Developmental and Metabolic Deficiencies Caused by Mutations in HNF1A.

Author information

1
Center for Cellular and Molecular Therapeutics, The Children's Hospital of Philadelphia, Philadelphia, PA, USA; Department of Biology, School of Arts and Sciences, University of Pennsylvania, Philadelphia, PA, USA.
2
Center for Cellular and Molecular Therapeutics, The Children's Hospital of Philadelphia, Philadelphia, PA, USA.
3
Department of Biology, School of Arts and Sciences, University of Pennsylvania, Philadelphia, PA, USA.
4
Center for Cellular and Molecular Therapeutics, The Children's Hospital of Philadelphia, Philadelphia, PA, USA; Department of Cell and Molecular Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
5
Center for Cellular and Molecular Therapeutics, The Children's Hospital of Philadelphia, Philadelphia, PA, USA; Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, and Division of Endocrinology, The Children's Hospital of Philadelphia, Philadelphia, PA, USA.
6
Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, and Division of Endocrinology, The Children's Hospital of Philadelphia, Philadelphia, PA, USA.
7
Center for Mitochondrial and Epigenomic Medicine, The Children's Hospital of Philadelphia, Philadelphia, PA, USA.
8
Department of Biomedical Engineering, Boston University, Boston, MA, USA.
9
Department of Biomedical Engineering, Boston University, Boston, MA, USA; The Wyss Institute for Biologically Inspired Engineering at Harvard University, Boston, MA, USA.
10
Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN, USA.
11
Division of Diabetes, Endocrinology, and Metabolism, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA.
12
Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN, USA; Division of Diabetes, Endocrinology, and Metabolism, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA; Veterans Affairs Tennessee Valley Healthcare System, Nashville, TN, USA.
13
Center for Cellular and Molecular Therapeutics, The Children's Hospital of Philadelphia, Philadelphia, PA, USA; Department of Pathology and Laboratory Medicine, The Children's Hospital of Philadelphia, Philadelphia, PA, USA.
14
Center for Cellular and Molecular Therapeutics, The Children's Hospital of Philadelphia, Philadelphia, PA, USA; Department of Pathology and Laboratory Medicine, The Children's Hospital of Philadelphia, Philadelphia, PA, USA. Electronic address: gaduep@email.chop.edu.

Abstract

Human monogenic diabetes, caused by mutations in genes involved in beta cell development and function, has been a challenge to study because multiple mouse models have not fully recapitulated the human disease. Here, we use genome edited human embryonic stem cells to understand the most common form of monogenic diabetes, MODY3, caused by mutations in the transcription factor HNF1A. We found that HNF1A is necessary to repress an alpha cell gene expression signature, maintain endocrine cell function, and regulate cellular metabolism. In addition, we identified the human-specific long non-coding RNA, LINKA, as an HNF1A target necessary for normal mitochondrial respiration. These findings provide a possible explanation for the species difference in disease phenotypes observed with HNF1A mutations and offer mechanistic insights into how the HNF1A gene may also influence type 2 diabetes.

KEYWORDS:

HNF1A; MODY3; beta cells; cell respiration; diabetes; embryonic stem cells; glycolysis; long non-coding RNA; pancreas

PMID:
31374199
DOI:
10.1016/j.stem.2019.07.007

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