Single-cell RNA-seq uncovers the pathological alterations of pancreatic islets in type 2 diabetes mice
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE200531 | GEO | 2022/04/09
REPOSITORIES: GEO
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Project description:Single-cell RNA-seq uncovers the pathological alterations of pancreatic islets in type 2 diabetes mice
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Project description:Little is known about the contribution of the epigenome to the pathophysiology of type 2 diabetes (T2D). Here we have used genome-wide DNA methylation profiling to obtain the first comprehensive DNA methylation data set for human T2D pancreatic islets. Therefore, we analyzed the methylation profile of 27,578 CpG sites affiliated to more than 14,000 genes in 16 samples of pancreatic islets, 11 normal and 5 type 2-diabetic. Keywords: DNA methylation Keywords: Methylation profiling by array We measured the methylation status of the 27,578 CpG sites (Human Methylation27 DNA BeadChip array) in genomic DNA obtained from pnacreatic islets of 11 non-diabetic and 5 type-2-diabetic male human donors to identify genes that are differentially methylated in T2D.
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Project description:Objective: beta-cell dedifferentiation has been revealed as a pathological mechanism underlying pancreatic dysfunction in diabetes. However, exactly how such dedifferentiation process affects beta-cell gene expression and islet microenvironment remains incompletely understood Method: We performed single-cell RNA-Sequencing (RNA-seq) in islets obtained from beta-cell-specific miR-7a2 overexpressing mice (Tg7), a murine model of beta-cell dedifferentiation and diabetes. Results: Single-cell RNA-seq revealed that beta-cell dedifferentiation is associated with the induction of genes associated with epithelial to mesenchymal transition (EMT) specifically in beta-cells of diabetic (12-week-old) Tg7 mice. These molecular changes are associated with a weakening of beta-cell:beta-cell contacts, increased extracellular matrix (ECM) deposition and TGFb-dependent islet fibrosis. We find that the mesenchymal reprogramming of beta-cells is explained in part by the downregulation of Pdx1 and its inability to regulate a myriad of target genes preserving the epithelial cell phenotype. Notable among epithelial genes transactivated by Pdx1 is Ovol2, a transcriptional repressor of the EMT transcription factor ZEB2. Following compromised beta-cell identity, the reduction of Pdx1 mRNA levels decreases Ovol2 gene expression, which triggers mesenchymal reprogramming of beta-cells through the induction of Zeb2. Finally, we provided evidence that EMT signalling associated with the upregulation of Zeb2 expression is a molecular feature of islet of T2D subjects. Conclusions: Our study indicates that beta-cell dedifferentiation triggers a chronic response to tissue injury, which alters the pancreatic islet microenvironment and contribute to islet fibrosis. It suggests that regulators of EMT signalling may represent novel therapeutic targets for the treatment of beta-cell dysfunction and fibrosis in T2D.
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