Dataset Information

Gene expression patterns in synchronized islet populations.

ABSTRACT: In vivo levels of insulin are oscillatory with a period of ~5-10 minutes, indicating that the islets of Langerhans within the pancreas are synchronized. While the synchronizing factors are still under investigation, one result of this behavior is expected to be coordinated and oscillatory intracellular factors, such as intracellular Ca²⁺ levels, throughout the islet population. In other cell types, oscillatory intracellular signals, like intracellular Ca²⁺, have been shown to affect specific gene expression. To test how the gene expression landscape may differ between a synchronized islet population with its reproducible intracellular oscillations and an unsynchronized islet population with heterogeneous oscillations, gene set enrichment analysis (GSEA) was used to compare an islet population that had been synchronized using a glucose wave with a 5-min period, and an unsynchronized islet population. In the population exposed to the glucose wave, 58/62 islets showed synchronization as evidenced by coordinated intracellular Ca²⁺ oscillations with an average oscillation period of 5.1 min, while in the unsynchronized population 29/62 islets showed slow oscillations with an average period of 5.2 min. The synchronized islets also had a significantly smaller drift of their oscillation period during the experiment as compared to the unsynchronized population. GSEA indicated that the synchronized population had reduced expression of gene sets related to protein translation, protein turnover, energy expenditure, and insulin synthesis, while those that were related to maintenance of cell morphology were increased.

SUBMITTER: Mukhitov N

PROVIDER: S-EPMC6548476 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Gene expression patterns in synchronized islet populations.

Mukhitov Nikita N Adablah Joel E JE Roper Michael G MG

Islets 20190503 2

In vivo levels of insulin are oscillatory with a period of ~5-10 minutes, indicating that the islets of Langerhans within the pancreas are synchronized. While the synchronizing factors are still under investigation, one result of this behavior is expected to be coordinated and oscillatory intracellular factors, such as intracellular Ca<sup>2+</sup> levels, throughout the islet population. In other cell types, oscillatory intracellular signals, like intracellular Ca<sup>2+</sup>, have been shown ...[more]

PMID: 31050588

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Project description:Aims/hypothesisMost type 2 diabetes-associated genetic variants identified via genome-wide association studies (GWASs) appear to act via the pancreatic islet. Observed defects in insulin secretion could result from an impact of these variants on islet development and/or the function of mature islets. Most functional studies have focused on the latter, given limitations regarding access to human fetal islet tissue. Capitalising upon advances in in vitro differentiation, we characterised the transcriptomes of human induced pluripotent stem cell (iPSC) lines differentiated along the pancreatic endocrine lineage, and explored the contribution of altered islet development to the pathogenesis of type 2 diabetes.MethodsWe performed whole-transcriptome RNA sequencing of human iPSC lines from three independent donors, at baseline and at seven subsequent stages during in vitro islet differentiation. Differentially expressed genes (q < 0.01, log2 fold change [FC] > 1) were assigned to the stages at which they were most markedly upregulated. We used these data to characterise upstream transcription factors directing different stages of development, and to explore the relationship between RNA expression profiles and genes mapping to type 2 diabetes GWAS signals.ResultsWe identified 9409 differentially expressed genes across all stages, including many known markers of islet development. Integration of differential expression data with information on transcription factor motifs highlighted the potential contribution of REST to islet development. Over 70% of genes mapping within type 2 diabetes-associated credible intervals showed peak differential expression during islet development, and type 2 diabetes GWAS loci of largest effect (including TCF7L2; log2FC = 1.2; q = 8.5 × 10-10) were notably enriched in genes differentially expressed at the posterior foregut stage (q = 0.002), as calculated by gene set enrichment analyses. In a complementary analysis of enrichment, genes differentially expressed in the final, beta-like cell stage of in vitro differentiation were significantly enriched (hypergeometric test, permuted p value <0.05) for genes within the credible intervals of type 2 diabetes GWAS loci.Conclusions/interpretationThe present study characterises RNA expression profiles during human islet differentiation, identifies potential transcriptional regulators of the differentiation process, and suggests that the inherited predisposition to type 2 diabetes is partly mediated through modulation of islet development.Data availabilitySequence data for this study has been deposited at the European Genome-phenome Archive (EGA), under accession number EGAS00001002721.

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Gene expression patterns in synchronized islet populations.

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Gene expression patterns in synchronized islet populations.

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