Type 2 diabetes is characterized by chronic hyperglycemia associated with impaired insulin action and secretion. Although the heritability of type 2 diabetes is high, the environment, including blood components, could play a major role in the development of the disease. Amongst environmental effects, epitranscriptomic modifications have been recently shown to affect gene expression and glucose homeostasis. The epitranscriptome is characterized by reversible chemical changes in RNA, with one of the most prevalent being the m6A methylation of RNA. Since pancreatic β cells fine tune glucose levels and play a major role in type 2 diabetes physiopathology, we hypothesized that the environment, through variations in blood glucose or blood free fatty acid concentrations, could induce changes in m6A methylation of RNAs in pancreatic β cells. Here we observe a significant decrease in m6A methylation upon high glucose concentration, both in mice and human islets, associated with altered expression levels of m6A demethylases. In addition, the use of siRNA and/or specific inhibitors against selected m6A enzymes demonstrate that these enzymes modulate the expression of genes involved in pancreatic β-cell identity and glucose-stimulated insulin secretion. Our data suggest that environmental variations, such as glucose, control m6A methylation in pancreatic β cells, playing a key role in the control of gene expression and pancreatic β-cell functions. Our results highlight novel causes and new mechanisms potentially involved in type 2 diabetes physiopathology and may contribute to a better understanding of the etiology of this disease.
The loss of pancreatic β-cell identity emerges as an important feature of type 2 diabetes development, but the molecular mechanisms are still elusive. Here, we explore the cell-autonomous role of the cell cycle regulator and transcription factor E2F1 in the maintenance of β-cell identity and insulin secretion. We show that the β-cell-specific loss of E2f1 function in mice triggers glucose intolerance associated with defective insulin secretion, an altered α-to-β-cell ratio, a downregulation of many β-cell genes and a concomitant increase of non-β-cell markers. Mechanistically, the epigenomic profiling of non-beta cell upregulated gene promoters identified an enrichment of bivalent H3K4me3/H3K27me3 or H3K27me3 marks. Conversely, downregulated genes were enriched in active chromatin H3K4me3 and H3K27ac histone marks. We find that histone deacetylase inhibitors modulate E2F1 transcriptional and epigenomic signatures associated with these β-cell dysfunctions. Finally, the pharmacological inhibition of E2F transcriptional activity in human islets also impairs insulin secretion and the expression of β-cell identity genes. Our data suggest that E2F1 is critical for maintaining β-cell identity through a sustained repression of non β-cell transcriptional programs.
The loss of pancreatic β-cell identity emerges as an important feature of type 2 diabetes development, but the molecular mechanisms are still elusive. Here, we explore the cellautonomous role of the cell cycle regulator and transcription factor E2F1 in the maintenance of β-cell identity, insulin secretion and glucose homeostasis. We show that the β-cell-specific loss of E2f1 function in mice triggers glucose intolerance associated with defective insulin secretion, an altered endocrine cell mass, a downregulation of many β-cell genes and a concomitant increase of non-β-cell markers. Mechanistically, the epigenomic profiling of promoters of these non-β-cell upregulated genes identified an enrichment of bivalent H3K4me3/H3K27me3 or H3K27me3 marks. Conversely, promoters of downregulated genes were enriched in active chromatin H3K4me3 and H3K27ac histone marks. We find that specific E2f1 transcriptional, cistromic and epigenomic signatures are associated with these β-cell dysfunctions, with E2F1 directly regulating several β-cell genes at the chromatin level. Finally, the pharmacological inhibition of E2F transcriptional activity in human islets also impairs insulin secretion and the expression of β-cell identity genes. Our data suggest that E2F1 is critical for maintaining β-cell identity and function through a sustained control of β-cell and non β-cell transcriptional programs.
Compromised β-cell function contributes to type 2 diabetes (T2D) development. The glucagon like peptide 1 (Glp-1) has emerged as a hormone with broad pharmacological potential toward T2D treatment, notably by improving β-cell functions. Recent data have shown that the transcription factor E2f1, besides its role as a cell cycle regulator, is involved in glucose homeostasis by modulating β-cell mass, function and identity. Here, we demonstrate a crosstalk between the E2F1, phosphorylation of retinoblastoma protein (pRb) and Glp-1 signaling pathways. We found that β-cell specific E2f1 deficient mice (E2f1β-/-) presented with impaired glucose homeostasis and decreased glucose stimulated-insulin secretion mediated by exendin 4 (i.e., GLP1R agonist), which were associated with decreased expression of Glp1r encoding Glp-1 receptor (GLP1R) in E2f1β-/- pancreatic islets. Decreasing E2F1 transcriptional activity with an E2F inhibitor in islets from nondiabetic humans decreased GLP1R levels and blunted the incretin effect of exendin 4 on insulin secretion. Conversely, overexpressing E2f1 in pancreatic β cells increased Glp1r expression associated with enhanced insulin secretion mediated by GLP1R agonist. Interestingly, kinome analysis of mouse islets demonstrated that an acute treatment with exendin 4 increased pRb phosphorylation and subsequent E2f1 transcriptional activity. This study suggests a molecular crosstalk between the E2F1/pRb and GLP1R signaling pathways that modulates insulin secretion and glucose homeostasis.
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