The TFEB – TGIF1 axis regulates EMT in mouse epicardial cells
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA739679 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
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| SRR14871077.fastq.gz | Fastqsanger.gz | |||
| SRR14871078.fastq.gz | Fastqsanger.gz |
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Project description:Epithelial-mesenchymal transition (EMT) is a complex and pivotal process involved in organogenesis and is related to several pathological processes, including cancer and fibrosis. During heart development, EMT mediates the conversion of epicardial cells into vascular smooth muscle cells and cardiac interstitial fibroblasts. Here, we show that the oncogenic transcription factor EB (TFEB) is a key regulator of EMT in epicardial cells and that its genetic overexpression in mouse epicardium is lethal due to heart defects linked to impaired EMT. TFEB specifically orchestrates the EMT-promoting function of transforming growth factor (TGF) β, and this effect results from activated transcription of thymine-guanine-interacting factor (TGIF)1, a TGFβ/Smad pathway repressor. The Tgif1 promoter is activated by TFEB, and in vitro and in vivo findings demonstrate its increased expression when Tfeb is overexpressed. Furthermore, Tfeb overexpression in vitro prevented TGFβ-induced EMT, and this effect was abolished by Tgif1 silencing. Tfeb loss of function, similar to that of Tgif1, sensitized cells to TGFβ, inducing an EMT response to low doses of TGFβ. Together, our findings reveal an unexpected function of TFEB in regulating EMT, which might provide new insights into injured heart repair and control of cancer progression.
2022-06-22 | GSE178575 | GEO
Project description:Epithelial-mesenchymal transition (EMT) is a complex and pivotal process involved in organogenesis and is related to several pathological processes, including cancer and fibrosis. During heart development, EMT mediates the conversion of epicardial cells into vascular smooth muscle cells and cardiac interstitial fibroblasts. Here, we show that the oncogenic transcription factor EB (TFEB) is a key regulator of EMT in epicardial cells and that its genetic overexpression in mouse epicardium is lethal due to heart defects linked to impaired EMT. TFEB specifically orchestrates the EMT-promoting function of transforming growth factor (TGF) β, and this effect results from activated transcription of thymine-guanine-interacting factor (TGIF)1, a TGFβ/Smad pathway repressor. The Tgif1 promoter is activated by TFEB, and in vitro and in vivo findings demonstrate its increased expression when Tfeb is overexpressed. Furthermore, Tfeb overexpression in vitro prevents TGFβ-induced EMT, and this effect is abolished by Tgif1 silencing. Tfeb loss of function, similar to that of Tgif1, sensitizes cells to TGFβ, inducing an EMT response to low doses of TGFβ. Together, our findings reveal an unexpected function of TFEB in regulating EMT, which might provide insights into injured heart repair and control of cancer progression.
| S-EPMC9440911 | biostudies-literature
Project description:The epicardium is a mesothelial layer covering the myocardium and contributes to different cardiac lineage descendants during cardiogenesis. Fine-tuned balanced signaling defines epicardial specification and regulates cell plasticity and cell-fate decisions of epicardial-derived cells (EPCDs) by epicardial-to-mesenchymal transition (EMT). However, powerful tools to investigate epicardial cell function, including markers with pivotal roles in developmental signaling, are still lacking. Here, we recapitulated embryonic epicardiogenesis using human induced pluripotent stem cells (hiPSCs) and identified type II classical cadherin CDH18 as a novel biomarker defining lineage specification in human developing epicardium. The loss of CDH18 led to the onset of EMT and specific differentiation towards cardiac smooth muscle cells. Furthermore, GATA4 regulated epicardial CDH18 expression. These results demonstrate the production and enrichment of hiPSC-derived epicardial cells via the tracing of CDH18 expression, providing a model for investigating epicardial function in human development and disease and enabling new possibilities for regenerative medicine.
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Project description:Epicardial cells undergo an epithelial-to-mesenchymal transtion (EMT) to generate coronary vascular smooth muscle cells (VSMC) and cardiac fibroblasts. Little is known about the mechanisms regulating EMT or the in vivo signals directing epicardial-derived cell (EPDC) fate. Here, we show that loss of PDGF signaling leads to a disruption in Sox9 expression, and when Sox9 expression was restored in mutant hearts, the EMT defect was rescued. Interestingly, mutants lacking only one of the PDGF genes exhibited a lineage specific requirement for the individual receptors. Loss of PDGFRα resulted in a deficit in cardiac fibroblast formation, while cVSMC development was unperturbed. Conversely, PDGFRβ was required for cVSMC development but not cardiac fibroblast development. Combined, our data demonstrate a novel role for PDGF receptors in epicardial EMT and EPDC development. GSM671723-GSM671724: Total RNA was isolated from E12.5 control and PDGF receptor epicardial knockout hearts using the Trizol reagent. RNA was processed as per manufacturer's instructions (Illumina Gene expression array, Illumina, inc. San Diego, CA, USA) GSM671877-GSM671882: Total RNA was isolated from E12.5 control and PDGF receptor epicardial knockout primary epicardial cultures using the Trizol reagent. RNA was processed as per manufacturer's instructions (Illumina Gene expression array, Illumina, inc. San Diego, CA, USA)
2011-02-28 | E-GEOD-27181 | biostudies-arrayexpress
Project description:Epicardial cells are progenitors giving rise to the majority of cardiac fibroblasts, coronary smooth muscle cells, and pericytes during cardiac development, and critically modulating heart morphogenesis and coronary development. An integral phase of epicardial cell fate transition is epithelial-to-mesenchymal transition (EMT), which confers motility and facilitates cell fate transition. We identify a pathway involving protein arginine methyltransferase 1 (PRMT1) and its downstream p53 signaling that drives epicardial EMT and invasion. We show that PRMT1 determines the half-life of p53 through regulating alternative splicing of Mdm4, which is a key controller of p53 degradation. Loss of PRMT1 promotes the expression of Mdm4 short form, which inhibits p53 degradation. Accumulation of p53 subsequently enhances Slug degradation and blocks epicardial EMT. We further demonstrated that the PRMT1-Mdm4-p53 pathway drives epicardial cell fate transition into cardiac fibroblasts, coronary smooth muscle cells and pericytes in vivo, and modulates ventricular morphogenesis and coronary vessel formation. Together, our results establish critical functions of the PRMT1-Mdm4-p53 pathway in epicardial EMT, invasion and cell fate transition.
2020-08-18 | GSE122200 | GEO
Project description:The transcription factor EB (TFEB) is a master regulator of lysosomal biogenesis and autophagy. We identify a distinct nuclear interactome of TFEB, with USP7 emerging as a key post-translational modulator of TFEB. Genetic depletion and inhibition of USP7 reveal its critical role in preserving TFEB stability within both nuclear and cytoplasmic compartments. Specifically, USP7 is identified as the deubiquitinase responsible for removing the K48-linked polyubiquitination signal from TFEB at lysine residues K116, K264, and K274, thereby preventing its proteasomal degradation. Functional assays demonstrate the involvement of USP7 in preserving TFEB-mediated transcriptional responses to nutrient deprivation, while also modulating autophagy flux and lysosome biogenesis. As USP7 is a deubiquitinase that protects TFEB from proteasomal degradation, these findings provide the foundation for therapeutic targeting of the USP7-TFEB axis in conditions characterized by TFEB dysregulation and metabolic abnormalities, particularly in certain cancers.
2024-09-17 | PXD055937 | Pride
Project description:Epicardial cells undergo an epithelial-to-mesenchymal transtion (EMT) to generate coronary vascular smooth muscle cells (VSMC) and cardiac fibroblasts. Little is known about the mechanisms regulating EMT or the in vivo signals directing epicardial-derived cell (EPDC) fate. Here, we show that loss of PDGF signaling leads to a disruption in Sox9 expression, and when Sox9 expression was restored in mutant hearts, the EMT defect was rescued. Interestingly, mutants lacking only one of the PDGF genes exhibited a lineage specific requirement for the individual receptors. Loss of PDGFRα resulted in a deficit in cardiac fibroblast formation, while cVSMC development was unperturbed. Conversely, PDGFRβ was required for cVSMC development but not cardiac fibroblast development. Combined, our data demonstrate a novel role for PDGF receptors in epicardial EMT and EPDC development.
2011-02-28 | GSE27181 | GEO
Project description:Nonmuscle myosin IIB (NMIIB; heavy chain encoded by MYH10) is essential for cardiac myocyte cytokinesis. The role of NMIIB in other cardiac cells is not known. Here, we show that NMIIB is required in epicardial formation and functions to support myocardial proliferation and coronary vessel development. Ablation of NMIIB in epicardial cells results in disruption of epicardial integrity with a loss of E-cadherin at cell-cell junctions and a focal detachment of epicardial cells from the myocardium. NMIIB-knockout and blebbistatin-treated epicardial explants demonstrate impaired mesenchymal cell maturation during epicardial epithelial-mesenchymal transition. This is manifested by an impaired invasion of collagen gels by the epicardium-derived mesenchymal cells and the reorganization of the cytoskeletal structure. Although there is a marked decrease in the expression of mesenchymal genes, there is no change in Snail (also known as Snai1) or E-cadherin expression. Studies from epicardium-specific NMIIB-knockout mice confirm the importance of NMIIB for epicardial integrity and epicardial functions in promoting cardiac myocyte proliferation and coronary vessel formation during heart development. Our findings provide a novel mechanism linking epicardial formation and epicardial function to the activity of the cytoplasmic motor protein NMIIB.
2017-07-21 | GSE101701 | GEO
Project description:In order to identify the effects of transcription factor EB (TFEB) overexpression on the liver transcriptome, we performed Affymetrix GeneChip hybridization experiments on injected mice overexpressing TFEB specifically in the liver. For the analysis of the injected mice overexpressing TFEB, total RNA was extracted from the liver of three mice. RNA extracted from the liver of 3 not-injected mice was used as a control.
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Project description:Nutrient sensing and adaptation in the placenta are essential for pregnancy viability and proper fetal growth. Our recent research demonstrates that the placenta adapts to nutrient insufficiency through mTOR inhibition-mediated trophoblast differentiation toward syncytiotrophoblasts (STBs), a highly specialized multinucleated trophoblast subtype directing extensive maternal-fetal interactions. However, the underlying mechanism remains elusive. Here, we unravel the indispensable role of the mTORC1 downstream transcriptional factor TFEB in STB formation both in vitro and in vivo. Endogenous TFEB deficiency significantly impaired STB differentiation in trophoblast cells and placenta organoids. Mechanistically, TFEB conferred direct transcriptional regulation of the fusogen ERVFRD-1 in human trophoblasts and thereby profoundly promoted STB formation, independent of its canonical function as a master regulator of the autophagy-lysosomal pathway. In line with the in vitro findings, systemic or trophoblast-specific deletion of Tfeb compromised STB formation and placental vascular construction, leading to severe embryonic lethality. Moreover, TFEB directs the trophoblast syncytialization response driven by mTORC1 signaling. Importantly, TFEB expression positively correlates with the reinforced trophoblast syncytialization in human fetal growth restriction (FGR) placentas exhibiting suppressed mTORC1 activity. Our findings substantiate that the TFEB-fusogen axis ensures proper STB formation during placenta development and under nutrient stress, shedding light on TFEB as a mechanistic link between nutrient-sensing machinery and trophoblast differentiation.
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