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
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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.
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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.
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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)
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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.
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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. 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.
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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.
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Project description:Epithelial-mesenchymal transition (EMT) fosters cancer cell invasion and metastasis, the main cause of cancer-related mortality. Growing evidence that SNAIL and ZEB transcription factors, typically portrayed as master regulators of EMT, may be dispensable for this process, led us to re-investigate its mechanistic underpinnings. For this, we used an unbiased computational ap-proach that integrated time-resolved analyses of chromatin structure and differential gene ex-pression, to predict transcriptional regulators of TGFβ1-inducible EMT in the MCF10A mam-mary epithelial cell line model. Bioinformatic analyses indicated comparatively minor contri-butions of SNAIL proteins and ZEB1 to TGFβ1-induced EMT, whereas the AP-1 subunit JUNB was anticipated to have a much larger impact. CRISPR/Cas9-mediated loss-of-function studies confirmed that TGFβ1-induced EMT proceeded independently of SNAIL proteins and ZEB1. In contrast, JUNB was necessary and sufficient for EMT in MCF10A cells, but not in A549 lung can-cer cells, indicating cell-type-specificity of JUNB EMT-regulatory capacity. Nonetheless, the JUNB-dependence of EMT-associated transcriptional reprogramming in MCF10A cells allowed to define a gene expression signature which was regulated by TGFβ1 in diverse cellular back-grounds, showed positively correlated expression with TGFβ signaling in multiple cancer tran-scriptomes, and was predictive of patient survival in several cancer types. Altogether, our find-ings provide novel mechanistic insights into the context-dependent control of TGFβ1-driven EMT and thereby may lead to improved diagnostic and therapeutic options.
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