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Epigenetic regulation of the MEG3-DLK1 microRNA cluster in human Type 2 diabetic islets

ABSTRACT: Type 2 diabetes mellitus (T2DM) is a complex disease characterized by the inability of the insulin-producing β-cells in the endocrine pancreas to overcome insulin resistance in peripheral tissues. To determine if microRNAs are involved in the pathogenesis of human T2DM, we sequenced the small RNAs of human islets from diabetic and non-diabetic organ donors. We identified a cluster of miRNAs in an imprinted locus on human chromosome 14q32 that is highly and specifically expressed in human β-cells and dramatically down-regulated in islets from T2DM organ donors. The down-regulation of this locus strongly correlates with hyper-methylation of its promoter. Using HITS-CLIP for the essential RISC-component Argonaute, we identified disease-relevant targets of the chromosome 14q32 microRNAs, such as IAPP and TP53INP1 that cause increased β-cell apoptosis upon over-expression in human islets. Our results support a role for microRNAs and their epigenetic control by DNA methylation in the pathogenesis of T2DM.

ORGANISM(S): Homo sapiens

PROVIDER: GSE51924 | GEO | 2013/11/22

SECONDARY ACCESSION(S): PRJNA229487

REPOSITORIES: GEO

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Epigenetic regulation of the MEG3-DLK1 microRNA cluster in human Type 2 diabetic islets

Project description:Type 2 diabetes mellitus (T2DM) is a complex disease characterized by the inability of the insulin-producing β-cells in the endocrine pancreas to overcome insulin resistance in peripheral tissues. To determine if microRNAs are involved in the pathogenesis of human T2DM, we sequenced the small RNAs of human islets from diabetic and non-diabetic organ donors. We identified a cluster of miRNAs in an imprinted locus on human chromosome 14q32 that is highly and specifically expressed in human β-cells and dramatically down-regulated in islets from T2DM organ donors. The down-regulation of this locus strongly correlates with hyper-methylation of its promoter. Using HITS-CLIP for the essential RISC-component Argonaute, we identified disease-relevant targets of the chromosome 14q32 microRNAs, such as IAPP and TP53INP1 that cause increased β-cell apoptosis upon over-expression in human islets. Our results support a role for microRNAs and their epigenetic control by DNA methylation in the pathogenesis of T2DM. Identification of miRNA-target interaction in human islets using HITS-CLIP, one mRNA library and one miRNA library

2013-11-22 | E-GEOD-51924 | biostudies-arrayexpress

Epigenetic regulation of the MEG3-DLK1 microRNA cluster in human Type 2 diabetic islets

Project description:Type 2 diabetes mellitus (T2DM) is a multi-factorial disease characterized by the inability of beta-cells in the endocrine pancreas to produce sufficient amounts of insulin to overcome insulin resistance in peripheral tissue. To investigate the function of miRNAs in T2DM, we sequenced the small RNAs of human islets cells from diabetic and non-diabetic organ donors and identified a cluster of miRNAs in an imprinted locus on human chromosome 14 to be dramatically down-regulated in T2DM islets. These miRNAs are highly and specifically expressed in human beta-cells. The down-regulation of this imprinted locus strongly correlates with increased methylation of its promoter in T2DM islets, providing evidence for an epigenetic modification that contributes to the pathogenesis of T2DM. Targets of the Chr 14q32 cluster of miRNAs were identified by high-throughput sequencing of cross-linked and immunoprecipitated RNA (HITS-CLIP) of Argonaute. We have also identified a unique class of sequences, termed chimeric reads, that represent an in vivo ligation of miRNAs and their targets while in complex with Argonaute, and which allow for the direct identification of miRNA:target relationships in vivo. There are three experiments in this submission. All are in human islets or islet cell types. The first is a comparison of miRNA levels in sorted alpha versus beta cells. There is one replicate for this experiment. The second experiment is to measure the expression of miRNAs in whole islets as a function of glucose levels. There are three levels and one replicate for each condition. The third exeriment is a comparison of whole islets taken from human donors that were suspected/confirmed Type 2 diabetic or considered controls. There are 3 controls and 4 T2D samples.

2013-12-01 | E-GEOD-52314 | biostudies-arrayexpress

Epigenetic regulation of the MEG3-DLK1 microRNA cluster in human Type 2 diabetic islets

2013-12-01 | GSE52314 | GEO

Gene expression in 832/13 INS1 beta-cells transduced with lentiviral vector conferring expression of GFP or Pax5

Project description:We found PAX5 to be overexpressed in human pancreatic islets of donors from donors with type 2 diabetes compared to islets from non-diabetic individuals. Functional follow-up showed that Pax5 overexpression in rat clonal beta-cells (832/13 INS1) results in impaired insulin secretion. Microarrays were used to investigate if overexpression of Pax5 alters the gene expression profile of 832/13 INS1 beta-cells.

2023-01-11 | GSE211310 | GEO

Identification of HIPs in the islets of mice and non-diabetic human donors

Project description:Hybrid insulin peptides (HIPs) result from the linkage of an insulin C-peptide fragment and another peptide via a traditional peptide bond to generate a sequence that is not encoded in the genome. Here, we sought to identify HIPs naturally present in the pancreatic islets of non-obese diabetic (NOD) mice, BALB/c mice, and non-diabetic human donors by mass spectrometry.

2019-01-07 | PXD011606 | Pride

Expression data comparing adult human islets to human embryonic stem cell-derived insulin-positive and insulin-negative cells

Project description:The study was completed to compare expression profiles of primary human beta cells (in the form of adult human islets), to the expression profile of hESC-derived beta-like cells. A HES3 line modified by homologous recombination to express GFP under the insulin promoter allowed us to FACS sort the hESC-derived cells into purified insulin-positive (presumably beta-like cells), and insulin-negative populations. Expression profile of adult human islets from cadaveric donors is compared to insulin-positive and insulin-negative populations of hESC-derived beta-like cells

2012-09-09 | E-GEOD-40709 | biostudies-arrayexpress

Transcription profiling of human pancreas from patients with type 1 diabetes (clinical onset and longstanding)

Project description:Type 1 diabetes is an autoimmune disease caused by the destruction of the insulin producing beta cells. We characterized the gene expression profile of pancreatic tissue from four type 1 diabetes patients (Cases 1-4), who died at different stages of the disease (onset and longstanding) by microarray analysis. All samples from patients and controls were obtained after death, at the time of organ donation. Pancreatic blocks from the four diabetic patients and three organ donors (Controls 1-3) were obtained and snap frozen. At the same time, islets from Cases 1 and 4 were isolated from a piece of the pancreas tail by enzymatic digestion (using automated method and handpicking) and snap frozen. Islets from three different organ donors (Controls 4-6) were obtained similarly to those of the diabetic patients. Both pancreatic blocks and islets were stored in liquid nitrogen until the mRNA extraction. For pancreas gene expression profiles, we compared data from three blocks of each of the four type 1 diabetic pancreas with pancreases data from the Controls 1-3. For islets expression profile, we compared data from Cases 1 and 4 islets with islets data from the Controls 4-6. <br><br>

2009-12-01 | E-MEXP-1140 | biostudies-arrayexpress

Phosphoproteomics reveals the GSK3-PDX1 axis as a key pathogenic signaling node in diabetic islets

Project description:Progressive decline of pancreatic beta cell function is central to the pathogenesis of type 2 diabetes. Protein phosphorylation regulates glucose-stimulated insulin secretion from beta cells, but how signaling networks are remodeled in diabetic islets in vivo remains unknown. Using high-sensitivity mass spectrometry-based proteomics we quantified 6,500 proteins and 13,000 phosphopeptides in islets of obese diabetic mice and matched controls, revealing drastic remodeling of key kinase hubs and signaling pathways. Integration with a literature-derived signaling network implicated GSK3 kinase in the control of the beta cell-specific transcription factor PDX1. Deep phosphoproteomic analysis of human islets chronically treated with high glucose demonstrated a conserved glucotoxicity-dependent role of GSK3 kinase in regulating insulin secretion. Remarkably, the ability of beta cells to secrete insulin in response to glucose was rescued almost completely by pharmacological inhibition of GSK3. Thus, our resource enables investigation of mechanisms and drug targets in type 2 diabetes.

2019-03-15 | PXD012671 | Pride

Diabetes Remission Using Glucose-Responsive Insulin-Producing Human alpha-Cells

Project description:Natural and stable cell identity switches, where terminally-differentiated cells convert into different cell-types when stressed, represent a widespread regenerative strategy in animals, yet they are poorly documented in mammals. In mice, some glucagon-producing pancreatic α-cells become insulin expressers upon ablation of insulin-secreting β-cells, promoting diabetes recovery. Whether human islets also display this plasticity for reconstituting β-like cells, especially in diabetic conditions, remains unknown. Here we show that two different islet non-β-cell types, α- and γ–cells, obtained from deceased non-diabetic or diabetic human donors can be lineage-traced and induced to produce insulin and secrete it in response to glucose. When transplanted into diabetic mice, converted human α-cells reverse diabetes and remain producing insulin even after 6 months. Insulin-producing α-cells maintain α-cell markers, as seen by deep transcriptomic and proteomic characterization, and display hypo-immunogenic features when exposed to T-cells derived from diabetic patients. These observations provide conceptual evidence and a molecular framework for a mechanistic understanding of in situ cell plasticity in islet cells, as well as in other organs, as a therapy for degenerative diseases by fostering the highly-regulated intrinsic cell regeneration.

2018-12-15 | GSE123844 | GEO

Diabetes Remission Using Glucose-Responsive Insulin-Producing Human α-Cells

2018-12-13 | GSE117454 | GEO

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