Dysregulation of a Pdx1/Ovol2/Zeb2 axis in dedifferentiated beta-cells triggers the induction of genes associated with epithelial-mesenchymal transition in diabetes
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA718854 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR14119303_1.fastq.gz | Fastqsanger.gz | |||
| SRR14119303_2.fastq.gz | Fastqsanger.gz | |||
| SRR14119304_1.fastq.gz | Fastqsanger.gz | |||
| SRR14119304_2.fastq.gz | Fastqsanger.gz | |||
| SRR14119305_1.fastq.gz | Fastqsanger.gz |
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Project description:Objectiveβ-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.MethodsWe 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.ResultsBulk 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.ConclusionsOur 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.
| S-EPMC8184664 | biostudies-literature
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 bulk in islets obtained from beta-cell-specific miR-7a2 overexpressing mice (Tg7), a murine model of beta-cell dedifferentiation and diabetes. Results: Bulk RNA-seq revealed that beta-cell dedifferentiation is associated with the induction of genes associated with epithelial to mesenchymal transition (EMT) in pre-diabetic (2-week-old) and diabetic (12-week-old) Tg7mice. 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.
2021-07-21 | GSE171251 | GEO
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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Project description:infarct size and subsequent deterioration in function. The identification of factors that enhance cardiac repair by the restoration of the vascular network is, therefore, of great significance. Here, we show that the transcription factor Zinc finger E-box-binding homeobox 2 (ZEB2) is increased in stressed cardiomyocytes and induces a cardioprotective cross-talk between cardiomyocytes and endothelial cells to enhance angiogenesis after ischemia. Single-cell sequencing indicates ZEB2 to be enriched in injured cardiomyocytes. Cardiomyocyte-specific deletion of ZEB2 results in impaired cardiac contractility and infarct healing post-myocardial infarction (post-MI), while cardiomyocyte-specific ZEB2 overexpression improves cardiomyocyte survival and cardiac function. We identified Thymosin 4 (TMSB4) and Prothymosin (PTMA) as main paracrine factors released from cardiomyocytes to stimulate angiogenesis by enhancing endothelial cell migration, and whose regulation is validated in our in vivo models. Therapeutic delivery of ZEB2 to cardiomyocytes in the infarcted heart induces the expression of TMSB4 and PTMA, which enhances angiogenesis and prevents cardiac dysfunction. These findings reveal ZEB2 as a beneficial factor during ischemic injury, which may hold promise for the identification of new therapies.
2021-03-23 | PXD022212 | Pride
Project description:Epithelial cells possess remarkable plasticity, having the ability to become mesenchymal cells through alterations in adhesion and motility (epithelial-to-mesenchymal transition or EMT). Recent studies suggest that EMT endows differentiated epithelial cells with stem cell traits, posing the interesting question of how epithelial plasticity is properly restricted to ensure epithelial differentiation during tissue morphogenesis. Here we identify zinc-finger transcription factor Ovol2 as a key suppressor of EMT of mammary epithelial cells. Epithelia-specific deletion of Ovol2 completely arrests mammary ductal morphogenesis, and depletes epithelial stem/progenitor cell reservoirs. Further, Ovol2-deficient epithelial cells undergo EMT in vivo to become non-epithelial cell types, and that Ovol2 directly represses key EMT inducers such as Zeb1 and regulates stem/progenitor cell responsiveness to TGF-beta. We also provide evidence for a suppressive role of Ovol2 in breast cancer progression. Our findings underscore the critical importance of exquisitely regulating epithelial plasticity to balance stemness with epithelial differentiation in development and cancer. We report ChIPseq data illustrating Ovol2 genome-wide targets in mouse mammary epithelial cells, suggesting that Ovol2 regulates a plethora of genes associated with the EMT process. Immunoprecipitated samples from HC11 mouse mammary epithelial cells with antibodies against Ovol2 and control IgG respectively were used for ChIP-seq experiments.
2014-03-19 | E-GEOD-53925 | biostudies-arrayexpress
Project description:We have demonstrated that the oncogenic activation of B-RAF (using a truncated delta-BRAF-ER version inducible with tamoxifen) in the melan-a melanocyte cell line triggers the activation of Zeb1 and Twist1 at the expanse of Zeb2 and Snail2. Enforced maintenance of Zeb2 or Snail2 expression reduces the B-RAF oncogenic potential while ectopic expression of Zeb1 or Twist1 cooperates with B-RAF in melan-a cell transformation. To get an insight into the properties of these embryonic transcription factors, gene expression profiles of melan-a-derived cell lines either expressing a non-activated B-RAF (- tamoxifen) or an activated BRAF (+ tamoxifen) alone or in combination with Snail2, Zeb2, Twist1 or Zeb1 have been established. Melan-a cells were transduced with an activated version of BRAF(delta-BRAF-ER, inducible with tamoxifen) alone or in combination with SNAIL2, ZEB2, ZEB1 or TWIST1. Gene expression profiles before or following BRAF activation (alone or in combination with the embryonic transcription factors) were determined. Ectopic expression of SNAIL2, ZEB2, ZEB1 or TWIST1 on BRAF-target genes in the murine melanocytic melan-a cell line.
2013-10-29 | E-GEOD-39030 | biostudies-arrayexpress
Project description:Epithelial cells possess remarkable plasticity, having the ability to become mesenchymal cells through alterations in adhesion and motility (epithelial-to-mesenchymal transition or EMT). Recent studies suggest that EMT endows differentiated epithelial cells with stem cell traits, posing the interesting question of how epithelial plasticity is properly restricted to ensure epithelial differentiation during tissue morphogenesis. Here we identify zinc-finger transcription factor Ovol2 as a key suppressor of EMT of mammary epithelial cells. Epithelia-specific deletion of Ovol2 completely arrests mammary ductal morphogenesis, and depletes epithelial stem/progenitor cell reservoirs. Further, Ovol2-deficient epithelial cells undergo EMT in vivo to become non-epithelial cell types, and that Ovol2 directly represses key EMT inducers such as Zeb1 and regulates stem/progenitor cell responsiveness to TGF-beta. We also provide evidence for a suppressive role of Ovol2 in breast cancer progression. Our findings underscore the critical importance of exquisitely regulating epithelial plasticity to balance stemness with epithelial differentiation in development and cancer. We report ChIPseq data illustrating Ovol2 genome-wide targets in mouse mammary epithelial cells, suggesting that Ovol2 regulates a plethora of genes associated with the EMT process.
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