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Induction of alpha cell-restricted Gc in dedifferentiating beta cells contributes to stress-induced beta-cell dysfunction [RNA-seq]

ABSTRACT: To identify effector genes of pancreatic beta cell dedifferentiation and dysfunction, we performed RNA expression in beta cells sorted from mice with multiparity-induced diabetes.

ORGANISM(S): Mus musculus

PROVIDER: GSE130997 | GEO | 2019/05/30

REPOSITORIES: GEO

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Induction of alpha cell-restricted Gc in dedifferentiating beta cells contributes to stress-induced beta-cell dysfunction [ChIP-seq]

Project description:To identify effector genes of pancreatic beta cell dedifferentiation and dysfunction, we integrated analyses of histone methylation as a surrogate of gene activation status and RNA expression in beta cells sorted from mice with multiparity-induced diabetes.

2019-05-30 | GSE130996 | GEO

Induction of α cell-restricted Gc in dedifferentiating β cells contributes to stress-induced β-cell dysfunction.

Project description:Diabetic β cell failure is associated with β cell dedifferentiation. To identify effector genes of dedifferentiation, we integrated analyses of histone methylation as a surrogate of gene activation status and RNA expression in β cells sorted from mice with multiparity-induced diabetes. Interestingly, only a narrow subset of genes demonstrated concordant changes to histone methylation and RNA levels in dedifferentiating β cells. Notable among them was the α cell signature gene Gc, encoding a vitamin D-binding protein. While diabetes was associated with Gc induction, Gc-deficient islets did not induce β cell dedifferentiation markers and maintained normal ex vivo insulin secretion in the face of metabolic challenge. Moreover, Gc-deficient mice exhibited a more robust insulin secretory response than normal controls during hyperglycemic clamps. The data are consistent with a functional role of Gc activation in β cell dysfunction, and indicate that multiparity-induced diabetes is associated with altered β cell fate.

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Induction of alpha cell-restricted Gc in dedifferentiating beta cells contributes to stress-induced beta-cell dysfunction [ChIP-seq]

Project description:Induction of alpha cell-restricted Gc in dedifferentiating beta cells contributes to stress-induced beta-cell dysfunction [ChIP-seq]

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Induction of alpha cell-restricted Gc in dedifferentiating beta cells contributes to stress-induced beta-cell dysfunction [RNA-seq]

Project description:Induction of alpha cell-restricted Gc in dedifferentiating beta cells contributes to stress-induced beta-cell dysfunction [RNA-seq]

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Induction and Reversal of beta-cell dysfunction

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Induction and Reversal of beta-cell dysfunction

Project description:INTRODUCTION: Targeting β-cell failure could prevent, delay or even partially reverse Type 2 Diabetes. However, development of such drugs is limited as the molecular pathogenesis is complex and incompletely understood. Further, while β-cell failure can be modelled experimentally only some of the molecular changes will be pathogenic. Therefore, we used a novel approach to identify molecular pathways that are not only changed in a diabetes-like state but are reversible and can be targeted by drugs. METHODS: INS1E cells were cultured in high glucose (20 mM) for 72 hrs or high glucose for an initial 24 hrs followed by drug addition (exendin-4, metformin and sodium salicylate) for the remaining 48 hrs. RNAseq (Illumina TruSeq), Gene Set Enrichment and Pathway Analyses (using Broad Institute, Reactome, KEGG and Biocarta platforms) was used to identify changes in molecular pathways. RESULTS: High glucose decreased function and increased apoptosis in INS1E cells with drugs partially reversing these effects. High glucose resulted in upregulation of 109 pathways while drug treatment downregulated 44 pathways with 21 pathways in common. Interestingly while hyperglycaemia extensively upregulated metabolic pathways, they were not altered with drug treatment, rather pathways involved in the cell cycle featured more heavily. CONCLUSION: GSEA for hyperglycaemia identified many known pathways validating the applicability of our cell model to human disease. However, only a fraction of these pathways were downregulated with drug treatment, highlighting the importance of considering druggable pathways. Overall, this provides a powerful approach and resource for identifying appropriate targets for the development of β-cell drugs.

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The Polycomb-dependent epigenome controls β-cell dysfunction, dedifferentiation and diabetes

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The Polycomb-dependent epigenome controls β-cell dysfunction, dedifferentiation and diabetes

Project description:To date, it remains largely unclear to what extent chromatin machinery contributes to the susceptibility and progression of complex diseases. Here, we combine deep epigenome mapping with single cell transcriptomics to mine for evidence of chromatin dysregulation in type-2 diabetes. We find two chromatin-state signatures that track β-cell dysfunction in mice and humans: ectopic activation of bivalent Polycomb-silenced domains and loss of expression at an epigenomically unique class of lineage-defining genes. β-cell specific Polycomb (Eed/PRC2) loss of function in mice triggers diabetes-mimicking transcriptional signatures and highly penetrant, hyperglycemia-independent, dedifferentiation, indicating that PRC2 dysregulation contributes to disease. The work provides novel resources for exploring β-cell transcriptional regulation and identifies PRC2 as necessary for long-term maintenance of β-cell identity. Importantly, the data suggest a two-hit (chromatin and hyperglycemia) model for loss of β-cell identity in diabetes.

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RNA Seq analysis of pancreatic beta cell transcriptome during dedifferentiation

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Progenitor Cell Marker Aldehyde Dehydrogenase 1a3 Defines a Subset of Failing Pancreatic Beta Cells in Diabetic Mice

Project description:Insulin-producing beta cells become dedifferentiated during diabetes progression. An impaired ability to select substrates for oxidative phosphorylation, or metabolic inflexibility, sets the stage for progression from beta cell dysfunction to beta cell dedifferentiation. In this study, we sought to isolate and functionally characterize failing beta cells, as a preliminary step to identify pathways to reverse dedifferentiation. Using various experimental models of diabetes, we found a striking enrichment in the expression of aldehyde dehydrogenase 1 isoform A3 (ALDH+) as beta cells become dedifferentiated. Flow-sorted ALDH+ islet cells demonstrate impaired glucose-induced insulin secretion, are depleted of Foxo1 and MafA, and include a Neurogenin3-positive subset. RNA sequencing analysis demonstrates that ALDH+ cells are characterized by: (i) impaired oxidative phosphorylation and mitochondrial complex I, IV, and V; (ii) activated RICTOR; and (iii) progenitor cell markers. We propose that impaired mitochondrial function marks the progression from metabolic inflexibility to dedifferentiation in the natural history of beta cell failure. RNA-Sequencing analysis of 2 different cell types in 2 different genotype categories.

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