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1.
Diabetes ; 71(7): 1525-1545, 2022 07 01.
Article in English | MEDLINE | ID: mdl-35476777

ABSTRACT

Impaired pancreatic ß-cell function and insulin secretion are hallmarks of type 2 diabetes. miRNAs are short, noncoding RNAs that silence gene expression vital for the development and function of ß cells. We have previously shown that ß cell-specific deletion of the important energy sensor AMP-activated protein kinase (AMPK) results in increased miR-125b-5p levels. Nevertheless, the function of this miRNA in ß cells is unclear. We hypothesized that miR-125b-5p expression is regulated by glucose and that this miRNA mediates some of the deleterious effects of hyperglycemia in ß cells. Here, we show that islet miR-125b-5p expression is upregulated by glucose in an AMPK-dependent manner and that short-term miR-125b-5p overexpression impairs glucose-stimulated insulin secretion (GSIS) in the mouse insulinoma MIN6 cells and in human islets. An unbiased, high-throughput screen in MIN6 cells identified multiple miR-125b-5p targets, including the transporter of lysosomal hydrolases M6pr and the mitochondrial fission regulator Mtfp1. Inactivation of miR-125b-5p in the human ß-cell line EndoCß-H1 shortened mitochondria and enhanced GSIS, whereas mice overexpressing miR-125b-5p selectively in ß cells (MIR125B-Tg) were hyperglycemic and glucose intolerant. MIR125B-Tg ß cells contained enlarged lysosomal structures and had reduced insulin content and secretion. Collectively, we identify miR-125b as a glucose-controlled regulator of organelle dynamics that modulates insulin secretion.


Subject(s)
Diabetes Mellitus, Type 2 , Insulin-Secreting Cells , MicroRNAs , AMP-Activated Protein Kinases/metabolism , Animals , Diabetes Mellitus, Type 2/genetics , Diabetes Mellitus, Type 2/metabolism , Glucose/metabolism , Glucose/pharmacology , Humans , Insulin-Secreting Cells/metabolism , Mice , MicroRNAs/genetics , MicroRNAs/metabolism
2.
Nat Genet ; 51(7): 1137-1148, 2019 07.
Article in English | MEDLINE | ID: mdl-31253982

ABSTRACT

Genetic studies promise to provide insight into the molecular mechanisms underlying type 2 diabetes (T2D). Variants associated with T2D are often located in tissue-specific enhancer clusters or super-enhancers. So far, such domains have been defined through clustering of enhancers in linear genome maps rather than in three-dimensional (3D) space. Furthermore, their target genes are often unknown. We have created promoter capture Hi-C maps in human pancreatic islets. This linked diabetes-associated enhancers to their target genes, often located hundreds of kilobases away. It also revealed >1,300 groups of islet enhancers, super-enhancers and active promoters that form 3D hubs, some of which show coordinated glucose-dependent activity. We demonstrate that genetic variation in hubs impacts insulin secretion heritability, and show that hub annotations can be used for polygenic scores that predict T2D risk driven by islet regulatory variants. Human islet 3D chromatin architecture, therefore, provides a framework for interpretation of T2D genome-wide association study (GWAS) signals.


Subject(s)
Chromatin/chemistry , Diabetes Mellitus, Type 2/genetics , Enhancer Elements, Genetic , Gene Expression Regulation , Gene Regulatory Networks , Insulin Secretion/genetics , Islets of Langerhans/metabolism , Chromatin/genetics , Cohort Studies , Diabetes Mellitus, Type 2/metabolism , Diabetes Mellitus, Type 2/pathology , Genetic Predisposition to Disease , Genome-Wide Association Study , Humans , Molecular Conformation , Promoter Regions, Genetic
3.
Cell Metab ; 25(2): 400-411, 2017 02 07.
Article in English | MEDLINE | ID: mdl-28041957

ABSTRACT

Recent studies have uncovered thousands of long non-coding RNAs (lncRNAs) in human pancreatic ß cells. ß cell lncRNAs are often cell type specific and exhibit dynamic regulation during differentiation or upon changing glucose concentrations. Although these features hint at a role of lncRNAs in ß cell gene regulation and diabetes, the function of ß cell lncRNAs remains largely unknown. In this study, we investigated the function of ß cell-specific lncRNAs and transcription factors using transcript knockdowns and co-expression network analysis. This revealed lncRNAs that function in concert with transcription factors to regulate ß cell-specific transcriptional networks. We further demonstrate that the lncRNA PLUTO affects local 3D chromatin structure and transcription of PDX1, encoding a key ß cell transcription factor, and that both PLUTO and PDX1 are downregulated in islets from donors with type 2 diabetes or impaired glucose tolerance. These results implicate lncRNAs in the regulation of ß cell-specific transcription factor networks.


Subject(s)
Gene Regulatory Networks/genetics , Insulin-Secreting Cells/metabolism , RNA, Long Noncoding/genetics , Chromatin/metabolism , Diabetes Mellitus, Type 2/genetics , Gene Expression Regulation , Gene Knockdown Techniques , Homeodomain Proteins/genetics , Homeodomain Proteins/metabolism , Humans , Insulin/metabolism , Insulin Secretion , Multigene Family , Phenotype , RNA, Long Noncoding/metabolism , RNA, Messenger/genetics , RNA, Messenger/metabolism , Trans-Activators/genetics , Trans-Activators/metabolism , Transcription Factors/metabolism , Transcription, Genetic
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