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Project description:Mesenchymal-to-epithelial transition (MET) is an important step in cell reprogramming from fibroblast, a most frequently used cell type for this purpose, to various epithelial cell types. However, how MET can be induced in fibroblast has not been fully studied. In this study, we sought for transcription factors (TFs) that can efficiently induce MET in dermal fibroblasts and identified OVOL2 as a potent inducer of key epithelial genes. In addition, OVOL2 cooperatively enhanced MET induced by HNF1A, TP63 and KLF4, known reprogramming TFs to epithelial lineages. In TP63/KLF4-induced fibroblast-keratinocyte cell reprogramming, OVOL2 greatly facilitated activation of epithelial genes as well as keratinocyte-specific genes. This enhancement of epithelial gene expression program was accompanied by enhanced changes in chromatin accessibility across the genome. Mechanistically, motif enrichment analysis revealed that target loci of KLF4 and TP63 become accessible upon reprogramming while OVOL2 target loci become inaccessible, indicating that KLF4 and TP63 positively regulate their targets while OVOL2 primarily induces closed chromatin state at its target loci. Thus, OVOL2 and tissue-specific reprogramming factors cooperatively facilitate cell reprogramming of fibroblast into epithelial lineages through distinct mechanisms.
2019-05-17 | GSE122034 | GEO
Project description:Mesenchymal-to-epithelial transition (MET) is an important step in cell reprogramming from fibroblast, a most frequently used cell type for this purpose, to various epithelial cell types. However, how MET can be induced in fibroblast has not been fully studied. In this study, we sought for transcription factors (TFs) that can efficiently induce MET in dermal fibroblasts and identified OVOL2 as a potent inducer of key epithelial genes. In addition, OVOL2 cooperatively enhanced MET induced by HNF1A, TP63 and KLF4, known reprogramming TFs to epithelial lineages. In TP63/KLF4-induced fibroblast-keratinocyte cell reprogramming, OVOL2 greatly facilitated activation of epithelial genes as well as keratinocyte-specific genes. This enhancement of epithelial gene expression program was accompanied by enhanced changes in chromatin accessibility across the genome. Mechanistically, motif enrichment analysis revealed that target loci of KLF4 and TP63 become accessible upon reprogramming while OVOL2 target loci become inaccessible, indicating that KLF4 and TP63 positively regulate their targets while OVOL2 primarily induces closed chromatin state at its target loci. Thus, OVOL2 and tissue-specific reprogramming factors cooperatively facilitate cell reprogramming of fibroblast into epithelial lineages through distinct mechanisms.
2019-05-17 | GSE122035 | GEO
Project description:Mesenchymal-to-epithelial transition (MET) is an important step in cell reprogramming from fibroblasts (a cell type frequently used for this purpose) to various epithelial cell types. However, the mechanism underlying MET induction in fibroblasts remains to be understood. The present study aimed to identify the transcription factors (TFs) that efficiently induce MET in dermal fibroblasts. OVOL2 was identified as a potent inducer of key epithelial genes, and OVOL2 cooperatively enhanced MET induced by HNF1A, TP63, and KLF4, which are known reprogramming TFs to epithelial lineages. In TP63/KLF4-induced keratinocyte-like cell-state reprogramming, OVOL2 greatly facilitated the activation of epithelial and keratinocyte-specific genes. This was accompanied by enhanced changes in chromatin accessibility across the genome. Mechanistically, motif enrichment analysis revealed that the target loci of KLF4 and TP63 become accessible upon induction of TFs, whereas the OVOL2 target loci become inaccessible. This indicates that KLF4 and TP63 positively regulate keratinocyte-associated genes whereas OVOL2 suppresses fibroblast-associated genes. The exogenous expression of OVOL2 therefore disrupts fibroblast lineage identity and facilitates fibroblast cell reprogramming into epithelial lineages cooperatively with tissue-specific reprogramming factors. Identification of OVOL2 as an MET inducer and an epithelial reprogramming enhancer in fibroblasts provides new insights into cellular reprogramming improvement for future applications.
| S-EPMC6482152 | biostudies-literature
Project description:Enhancement of direct reprogramming from fibroblasts to epithelial lineages by OVOL2-induced mesenchymal-to-epithelial transition
| PRJNA503197 | ENA
Project description:Enhancement of direct reprogramming from fibroblasts to epithelial lineages by OVOL2-induced mesenchymal-to-epithelial transition [CAGE]
| PRJNA503198 | ENA
Project description:Enhancement of direct reprogramming from fibroblasts to epithelial lineages by OVOL2-induced mesenchymal-to-epithelial transition [ATAC-seq]
| PRJNA503199 | ENA
Project description:Metastatic progression, including extravasation and micrometastatic outgrowth, is the main cause of cancer patient death. Recent studies suggest that cancer cells reprogram their metabolism to support increased proliferation through increased glycolysis and biosynthetic activities, including lipogenesis pathways. However, metabolic changes during metastatic progression, including alterations in regulatory gene expression, remain undefined. We show that transforming growth factor beta 1 (TGFβ1)-induced epithelial-to-mesenchymal transition (EMT) is accompanied by coordinately reduced enzyme expression required to convert glucose into fatty acids, and concomitant enhanced respiration. Overexpressed Snail1, a transcription factor mediating TGFβ1-induced EMT, was sufficient to suppress carbohydrate-responsive-element-binding protein (ChREBP, a master lipogenic regulator), and fatty acid synthase (FASN), its effector lipogenic gene. Stable FASN knockdown was sufficient to induce EMT, stimulate migration and extravasation in vitro. FASN silencing enhanced lung metastasis and death in vivo. These data suggest that a metabolic transition that suppresses lipogenesis and favors energy production is an essential component of TGFβ1-induced EMT and metastasis.
| S-EPMC4387121 | biostudies-literature
Project description:Metastasis is the most frequent cause of death in cancer patients. Epithelial-to-mesenchymal transition (EMT) is the process in which cells lose epithelial integrity and become motile, a critical step for cancer cell invasion, drug resistance and immune evasion. The transforming growth factor-β (TGFβ) signaling pathway is a major driver of EMT. Increasing evidence demonstrates that metabolic reprogramming is a hallmark of cancer and extensive metabolic changes are observed during EMT. The aim of this review is to summarize and interconnect recent findings that illustrate how changes in glycolysis, mitochondrial, lipid and choline metabolism coincide and functionally contribute to TGFβ-induced EMT. We describe TGFβ signaling is involved in stimulating both glycolysis and mitochondrial respiration. Interestingly, the subsequent metabolic consequences for the redox state and lipid metabolism in cancer cells are found to be in favor of EMT as well. Combined we illustrate that a better understanding of the mechanistic links between TGFβ signaling, cancer metabolism and EMT holds promising strategies for cancer therapy, some of which are already actively being explored in the clinic.
| S-EPMC7256023 | biostudies-literature
Project description:The cytokine transforming growth factor-β (TGF-β) can induce normal breast epithelial cells to take on a mesenchymal phenotype, termed epithelial-to-mesenchymal transition (EMT). While the transcriptional and proteomic changes during TGF-β-induced EMT have been described, the metabolic rewiring that occurs in epithelial cells undergoing EMT is not well understood. Here, we quantitively analyzed the TGF-β-induced metabolic reprogramming during EMT of non-transformed NMuMG mouse mammary gland epithelial cells using nuclear magnetic resonance (NMR) spectroscopy. We found that TGF-β elevates glycolytic and tricarboxylic acid (TCA)-cycle activity and increases glutaminolysis. Additionally, TGF-β affects the hexosamine pathway, arginine-proline metabolism, the cellular redox state, and strongly affects choline metabolism during EMT. TGF-β was found to induce phosphocholine production. A kinase inhibitor RSM-93A that inhibits choline kinase α (CHKα) mitigated TGF-β-induced changes associated with EMT, i.e., increased filamentous (F)-actin stress fiber formation and N-Cadherin mesenchymal marker expression.
| S-EPMC8464788 | biostudies-literature
Project description:Cell plasticity regulated by the balance between the mesenchymal to epithelial transition (MET) and the opposite program, EMT, is critical in the metastatic cascade. Several transcription factors (TFs) are known to regulate EMT, though the mechanisms of MET remain unclear. We demonstrate a novel function of two TFs, OVOL1 and OVOL2, as critical inducers of MET in human cancers. Our findings indicate that the OVOL-TFs control MET through a regulatory feedback loop with EMT-inducing TF ZEB1, and the regulation of mRNA splicing by inducing Epithelial Splicing Regulatory Protein 1 (ESRP1). Using mouse prostate tumor models we show that expression of OVOL-TFs in mesenchymal prostate cancer cells attenuates their metastatic potential. The role of OVOL-TFs as inducers of MET is further supported by expression analyses in 917 cancer cell lines, suggesting their role as crucial regulators of epithelial-mesenchymal cell plasticity in cancer.
| S-EPMC3790720 | biostudies-literature