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:The global prevalence of type 2 diabetes (T2D) is increasing, and it is contributing to the susceptibility to diabetes and its related epidemic in offspring. Although the impacts of paternal T2D on metabolism of offspring have been well established, the exact molecular and mechanistic basis that mediates these impacts remains largely unclear. Here we show that paternal T2D increases the susceptibility to diabetes in offspring through the gametic epigenetic alterations. Paternal T2D led to glucose intolerance and insulin resistance in offspring. Relative to controls, offspring of T2D fathers exhibited altered gene expression patterns in the pancreatic islets, with downregulation of several genes involved in glucose metabolism and insulin signaling pathway. Epigenomic profiling of offspring pancreatic islets revealed numerous changes in cytosine methylation depending on paternal T2D, including reproducible changes in methylation over several insulin signaling genes. Paternal T2D altered overall methylome patterns in sperm, with a large portion of differentially methylated genes overlapped with that of pancreatic islets in offspring. Our study revealed, for the first time, that T2D can be inherited transgenerationally through the mammalian germline by an epigenetic manner. Examination of the effect of paternal T2D on the DNA methylation in the pancreatic islets of offspring and in the sperm of father.
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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: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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