Zeb1 regulates mammary basal epithelial fate and proliferation dynamics through modulating EMT gene expression and Wnt signaling
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ABSTRACT:
PROVIDER: PRJNA650521 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| Other | ||||
| SRR12375900_1.fastq.gz | Fastqsanger.gz | |||
| SRR12375900_2.fastq.gz | Fastqsanger.gz | |||
| SRR12375901_1.fastq.gz | Fastqsanger.gz | |||
| SRR12375901_2.fastq.gz | Fastqsanger.gz |
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Project description:Molecular/cellular events that associate with epithelial-to-mesenchymal transition (EMT) are linked to acquisition of cancer stem cell traits, but whether EMT mechanisms regulate tissue epithelial cell fate and stem cell activity in vivo remains ambiguous. Using single-cell RNA sequencing, we detect heterogeneous EMT gene expression in stem cell-containing mammary basal/myoepithelial cells that normally possess both epithelial and smooth muscle characteristics. We show that EMT-inducing transcription factor Zeb1 is required within the mammary epithelium for ductal branching morphogenesis and regeneration, and that it promotes basal cell fate and regulates stem cell proliferation dynamics. We provide genetic and molecular evidence for EMT-dependent and -independent mechanisms of Zeb1 function, and show that Zeb1 cooperates with YAP to directly activate targets that inhibit Wnt signaling or control cell cycle. Together, our findings underscore Zeb1-mediated EMT control in governing mammary basal cell fate and proliferative activity, but with an interesting turn that involves mechanisms beyond EMT.
2022-03-08 | GSE155628 | GEO
Project description:Molecular/cellular events that associate with epithelial-to-mesenchymal transition (EMT) are linked to acquisition of cancer stem cell traits, but whether EMT mechanisms regulate tissue epithelial cell fate and stem cell activity in vivo remains ambiguous. Using single-cell RNA sequencing, we detect heterogeneous EMT gene expression in stem cell-containing mammary basal/myoepithelial cells that normally possess both epithelial and smooth muscle characteristics. We show that EMT-inducing transcription factor Zeb1 is required within the mammary epithelium for ductal branching morphogenesis and regeneration, and that it promotes basal cell fate and regulates stem cell proliferation dynamics. We provide genetic and molecular evidence for EMT-dependent and -independent mechanisms of Zeb1 function, and show that Zeb1 cooperates with YAP to directly activate targets that inhibit Wnt signaling or control cell cycle. Together, our findings underscore Zeb1-mediated EMT control in governing mammary basal cell fate and proliferative activity, but with an interesting turn that involves mechanisms beyond EMT.
2022-03-08 | GSE188781 | GEO
Project description:Epithelial-mesenchymal transition (EMT) involves profound changes in cell morphology, driven by transcriptional and epigenetic reprogramming. However, it emerges that translation and the ribosome composition play also key role in establishing physio-pathological phenotypes. Using genome-wide analyses, we report significant rearrangement of the translational landscape and machinery during EMT. Specifically, a mesenchymal cell line overexpressing the EMT transcription factor ZEB1 shows alterations in translational reprogramming and fidelity. Considering the change in translational activity of ZEB1-overexpressing mesenchymal cells, including in fidelity activity, we sought for changes in ribosome composition. We thus performed a riboproteome approach, i.e., mass spectrometry (MS)-based quantitative proteomic analysis of purified cytoplasmic ribosomes to highlight any change in relative amount of individual ribosomal proteins between wild-type and ZEB1-overexpressing human mammary epithelial cells.
2024-11-02 | PXD047409 | Pride
Project description:Epithelial-to-mesenchymal transition (EMT) is a fundamental process in development and disease. If aberrantly activated it is a trigger for tumour progression and metastasis (Thiery et al 2009 Cell). It is now known that EMT activation is also associated with the maintenance of stem-cell properties (Mani et al. 2008 Cell). Since Zinc-finger enhancer binding transcription factor 1 (ZEB1) is a crucial EMT activator, we analyzed the changes in the gene expression profile that accompany shRNA mediated loss of ZEB1 in MDA MB 231 basal type breast cancer cells. MDA MB 231 is a cell line that exhibits mesenchymal characteristics, but reverts to an epithelial phenotype upon ZEB1 knock down (Spaderna et al. 2008 Cancer Research). MDA MB 231 cells were stably transfected with control (GFP) or ZEB1 shRNA. Upon puromycin selection, single cell clones were picked and characterized. Cells from two control versus two ZEB1 knockdown clones were harvested, total RNA was isolated and processed to hybridization.
2015-09-15 | E-MTAB-3482 | biostudies-arrayexpress
Project description:Cell plasticity is emerging as a key regulator of tumor progression and metastasis. During carcinoma dissemination epithelial cells undergo epithelial to mesenchymal transition (EMT) processes characterized by the acquisition of migratory/invasive properties, while the reverse, mesenchymal to epithelial transition (MET) process, is also essential for metastasis outgrowth. Different transcription factors, called EMT-TFs, including Snail, bHLH and Zeb families are drivers of the EMT branch of epithelial plasticity, and can be post-transcriptionally downregulated by several miRNAs, as the miR-200 family. The specific or redundant role of different EMT-TFs and their functional interrelations are not fully understood. To study the interplay between different EMT-TFs, comprehensive gain and loss-of-function studies of Snail1, Snail2 and/or Zeb1 factors were performed in the prototypical MDCK cell model system. We here describe that Snail1 and Zeb1 are mutually required for EMT induction while continuous Snail1 and Snail2 expression, but not Zeb1, is needed for maintenance of the mesenchymal phenotype in MDCK cells. In this model system, EMT is coordinated by Snail1 and Zeb1 through transcriptional and epigenetic downregulation of the miR-200 family. Interestingly, Snail1 is involved in epigenetic CpG DNA methylation of the miR-200 loci, essential to maintain the mesenchymal phenotype. The present results thus define a novel functional interplay between Snail and Zeb EMT-TFs in miR200f regulation providing a molecular link to their previous involvement in the generation of EMT process in vivo. Expression analysis of MDCK over-expression EMT-TF Analysis of 7 overexpression MDCK cells each of them using biological rpelicates (MDCK-E47, Snail2, Snail1, Twist1, Tiwst2, Zeb1, Zeb2)
2014-09-09 | E-GEOD-61217 | biostudies-arrayexpress
Project description:The prostate basal cell compartment is postulated to contain stem/progenitors due to its resistance to castration, capability to differentiation into basal, luminal and neuroendocrine cell lineages of prostate epithelium, and susceptibility to oncogenic transformation. However, the heterogeneity and the interrelationship among different cell subpopulations within prostate basal cells remain largely unknow. Here we find that the core epithelial-to-mesenchymal transition (EMT) inducer Zeb is exclusively expressed in a prostate basal cell subpopulation. The Zeb1+ basal cells are resistant against androgen deprivation, possess greater efficiency to produce prostate spheroids in vitro, undergo self-renewal, and can generate functional prostate with all three cell lineages in vivo at the single cell level. Utilizing unbiased single cell transcriptomic analysis of over 9000 mouse prostate basal cells, we find that Zeb1+ basal cell subset shares gene expression profile with both epithelial and mesenchymal cells and stands out uniquely among all the cell clusters. Pseudotemporal reconstruction revealed three cell lineage trajectories through which the Zeb1+ basal cell subset gives rise to differentiated basal cells, and androgen dependent or independent intermediate cells. at the starting point in the developmental trajectories of cell clusters in prostate basal epithelium. In addition, Zeb1 positive basal cells can be detected in human prostate samples. Our data demonstrate that these Zeb1+ cells are bona fide PSCs in the basal cell compartment. Identification of the prostate stem cell (PSC) and its differentiation path is crucial to advance our understanding of prostate development and tumorigenesis.
2019-03-01 | GSE111429 | GEO
Project description:Cell plasticity is emerging as a key regulator of tumor progression and metastasis. During carcinoma dissemination epithelial cells undergo epithelial to mesenchymal transition (EMT) processes characterized by the acquisition of migratory/invasive properties, while the reverse, mesenchymal to epithelial transition (MET) process, is also essential for metastasis outgrowth. Different transcription factors, called EMT-TFs, including Snail, bHLH and Zeb families are drivers of the EMT branch of epithelial plasticity, and can be post-transcriptionally downregulated by several miRNAs, as the miR-200 family. The specific or redundant role of different EMT-TFs and their functional interrelations are not fully understood. To study the interplay between different EMT-TFs, comprehensive gain and loss-of-function studies of Snail1, Snail2 and/or Zeb1 factors were performed in the prototypical MDCK cell model system. We here describe that Snail1 and Zeb1 are mutually required for EMT induction while continuous Snail1 and Snail2 expression, but not Zeb1, is needed for maintenance of the mesenchymal phenotype in MDCK cells. In this model system, EMT is coordinated by Snail1 and Zeb1 through transcriptional and epigenetic downregulation of the miR-200 family. Interestingly, Snail1 is involved in epigenetic CpG DNA methylation of the miR-200 loci, essential to maintain the mesenchymal phenotype. The present results thus define a novel functional interplay between Snail and Zeb EMT-TFs in miR200f regulation providing a molecular link to their previous involvement in the generation of EMT process in vivo. Expression analysis of MDCK over-expression EMT-TF
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Project description:This SuperSeries is composed of the SubSeries listed below.
2022-03-08 | GSE155636 | GEO
Project description:This SuperSeries is composed of the SubSeries listed below. Zinc finger E-box binding protein 1 (ZEB1) and ZEB2 induce epithelial-mesenchymal transition (EMT) and cancer progression. However, little is known about global picture of transcriptional regulation by ZEB1 and ZEB2. Here we identified an inflammatory phenotype regulated by ZEB1 using chromatin immunoprecipitation-sequencing (ChIP-seq) and RNA-sequencing (RNA-seq) in basal type breast cancer cells, followed by gene set enrichment analysis (GSEA) of ZEB1-bound genes.
2017-06-16 | GSE89206 | GEO
Project description:Therapy resistance and metastasis, the most fatal steps in cancer, are often triggered by a (partial) activation of the epithelial-mesenchymal-transition (EMT)-program. A mesenchymal phenotype predisposes to ferroptosis, a cell death pathway exerted by an iron and oxygen-radical mediated peroxidation of phospholipids containing polyunsaturated fatty acids (PUFAs). We here describe that various forms of EMT-activation, including TGFB-stimulation, increase ferroptosis-susceptibility in cancer cells, which depends on the EMT-transcription factor Zeb1. Among other effects, we demonstrate that Zeb1 increases the ratio of phospholipids containing pro-ferroptotic PUFAs over cyto-protective monounsaturated fatty acids (MUFAs) and modulates the expression of underlying crucial lipogenic enzymes (and ACSL4). Pharmacological inhibition of selected lipogenic enzymes (SCD and FADS2) allows the manipulation of ferroptosis-sensitivity in a Zeb1-dependent manner. Our data are of potential translational relevance and suggest a combination of ferroptosis-activators and SCD-inhibitors for the treatment of aggressive cancers expressing Zeb1, which might also be a useful predictive marker for such a combination therapy
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