Dysregulation of the Pdx1/Ovol2/Zeb2 axis in dedifferentiated β-cells triggers the induction of genes associated with epithelial–mesenchymal transition in diabetes

Molecular Metabolism

Tracy C.S. Mak¹  Alejandra Tomas¹  Yorrick von Ohlen¹  Pauline Chabosseau¹  Walter Distaso¹  Eva Kane²  Daniel S. de Jesus²  Yi-Fang Wang²  Victoria Salem²  Catherine M. Chahrour²  Guy A. Rutter³  Ying Bai³  Mathieu Latreille⁴  Markus Stoffel⁴ 

[1] Institute of Clinical Sciences (ICS), Faculty of Medicine, Imperial College London, Du Cane Road, London W12 0NN, UK;Cellular Identity and Metabolism Group, MRC London Institute of Medical Sciences, Du Cane Road, London W12 0NN, UK;Computing and Bioinformatics Facility, MRC London Institute of Medical Sciences, Du Cane Road, London W12 0NN, UK;Imperial College Business School, London, UK;

关键词: Diabetes;    Insulin;    Pancreatic β-cells;    Dedifferentiation;    Epithelial-to-mesenchymal transition;    microRNA;   

DOI  :  

来源: DOAJ

【 摘 要 】

Objective: β-cell dedifferentiation has been revealed as a pathological mechanism underlying pancreatic dysfunction in diabetes. We previously showed that increased miR-7 levels trigger β-cell dedifferentiation and diabetes. We used β-cell-specific miR-7 overexpressing mice (Tg7) to test the hypothesis that loss of β-cell identity triggered by miR-7 overexpression alters islet gene expression and islet microenvironment in diabetes. Methods: We performed bulk and single-cell RNA sequencing (RNA-seq) in islets obtained from β-cell-specific miR-7 overexpressing mice (Tg7). We carried out loss- and gain-of-function experiments in MIN6 and EndoC-bH1 cell lines. We analysed previously published mouse and human T2D data sets. Results: Bulk RNA-seq revealed that β-cell dedifferentiation is associated with the induction of genes associated with epithelial-to-mesenchymal transition (EMT) in prediabetic (2-week-old) and diabetic (12-week-old) Tg7 mice. Single-cell RNA-seq (scRNA-seq) indicated that this EMT signature is enriched specifically in β-cells. These molecular changes are associated with a weakening of β-cell: β-cell contacts, increased extracellular matrix (ECM) deposition, and TGFβ-dependent islet fibrosis. We found that the mesenchymal reprogramming of β-cells is explained in part by the downregulation of Pdx1 and its inability to regulate a myriad of epithelial-specific genes expressed in β-cells. Notable among genes transactivated by Pdx1 is Ovol2, which encodes a transcriptional repressor of the EMT transcription factor Zeb2. Following compromised β-cell identity, the reduction in Pdx1 gene expression causes a decrease in Ovol2 protein, triggering mesenchymal reprogramming of β-cells through the induction of Zeb2. We provided evidence that EMT signalling associated with the upregulation of Zeb2 expression is a molecular feature of islets in T2D subjects. Conclusions: Our study indicates that miR-7-mediated β-cell dedifferentiation induces EMT signalling and a chronic response to tissue injury, which alters the islet microenvironment and predisposes to fibrosis. This research suggests that regulators of EMT signalling may represent novel therapeutic targets for treating β-cell dysfunction and fibrosis in T2D.

【 授权许可】

Unknown