Imperial College London
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Dr Alejandra Tomas

Faculty of Medicine, Department of Metabolism, Digestion and Reproduction

Senior Lecturer
 
 
 
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Contact

 

+44 (0)20 7594 3364a.tomas-catala Website CV

 
 
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Location

 

329ICTEM buildingHammersmith Campus

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Summary

 

Publications

Citation

BibTex format

@article{de:2021:10.1016/j.molmet.2021.101248,
author = {de, Jesus DS and Mak, TCS and Wang, Y-F and von, Ohlen Y and Bai, Y and Kane, E and Chabosseau, P and Chahrour, CM and Distaso, W and Salem, V and Tomas, A and Stoffel, M and Rutter, GA and Latreille, M},
doi = {10.1016/j.molmet.2021.101248},
journal = {Molecular Metabolism},
title = {Dysregulation of the Pdx1/Ovol2/Zeb2 axis in dedifferentiated β-cells triggers the induction of genes associated with epithelial-mesenchymal transition in diabetes},
url = {http://dx.doi.org/10.1016/j.molmet.2021.101248},
volume = {53},
year = {2021}
}
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RIS format (EndNote, RefMan)

TY  - JOUR
AB  - 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 m
AU  - de,Jesus DS
AU  - Mak,TCS
AU  - Wang,Y-F
AU  - von,Ohlen Y
AU  - Bai,Y
AU  - Kane,E
AU  - Chabosseau,P
AU  - Chahrour,CM
AU  - Distaso,W
AU  - Salem,V
AU  - Tomas,A
AU  - Stoffel,M
AU  - Rutter,GA
AU  - Latreille,M
DO  - 10.1016/j.molmet.2021.101248
PY  - 2021///
SN  - 2212-8778
TI  - Dysregulation of the Pdx1/Ovol2/Zeb2 axis in dedifferentiated β-cells triggers the induction of genes associated with epithelial-mesenchymal transition in diabetes
T2  - Molecular Metabolism
UR  - http://dx.doi.org/10.1016/j.molmet.2021.101248
UR  - https://www.ncbi.nlm.nih.gov/pubmed/33989778
UR  - http://hdl.handle.net/10044/1/90362
VL  - 53
ER  -
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