Modeling Monogenic Diabetes using Human ESCs Reveals Developmental and Metabolic Deficiencies Caused by Mutations in HNF1A.
HNF1A
MODY3
beta cells
cell respiration
diabetes
embryonic stem cells
glycolysis
long non-coding RNA
pancreas
Journal
Cell stem cell
ISSN: 1875-9777
Titre abrégé: Cell Stem Cell
Pays: United States
ID NLM: 101311472
Informations de publication
Date de publication:
01 08 2019
01 08 2019
Historique:
received:
18
07
2018
revised:
13
03
2019
accepted:
15
07
2019
entrez:
3
8
2019
pubmed:
3
8
2019
medline:
15
8
2020
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 31374199
pii: S1934-5909(19)30305-4
doi: 10.1016/j.stem.2019.07.007
pmc: PMC6785828
mid: NIHMS1535675
pii:
doi:
Substances chimiques
HNF1A protein, human
0
Hepatocyte Nuclear Factor 1-alpha
0
Milk Proteins
0
Monogen
0
RNA, Long Noncoding
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.
Langues
eng
Sous-ensembles de citation
IM
Pagination
273-289.e5Subventions
Organisme : NIDDK NIH HHS
ID : K12 DK094723
Pays : United States
Organisme : NIDDK NIH HHS
ID : R01 DK118155
Pays : United States
Organisme : NIDDK NIH HHS
ID : R01 DK092113
Pays : United States
Organisme : NIDDK NIH HHS
ID : P30 DK020593
Pays : United States
Organisme : NICHD NIH HHS
ID : U54 HD086984
Pays : United States
Organisme : NIBIB NIH HHS
ID : R01 EB008396
Pays : United States
Organisme : NIDDK NIH HHS
ID : UC4 DK104196
Pays : United States
Informations de copyright
Copyright © 2019 Elsevier Inc. All rights reserved.
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