ZEB1-regulated inflammatory phenotype in breast cancer cells
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE89206 | GEO | 2017/06/16
SECONDARY ACCESSION(S): PRJNA350678
REPOSITORIES: GEO
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Project description:The epithelial–mesenchymal transition (EMT) is a dynamic transdifferentiation of epithelial cells into mesenchymal cells. EMT programs exhibit great diversity, based primarily on the distinct impact of molecular activities of the EMT transcription factors. Using a panel of cancer cell lines and a series of 71 triple-negative primary breast tumors, we report that the EMT transcription factor ZEB1 modulates site-specific chemical modifications of ribosomal RNA (rRNA). Overexpression of ZEB1 and ZEB2, but not TWIST1, decreased the level of 2′-O-ribose methylation (2′Ome) of 28S rRNA at position Um2402. ZEB1 overexpression specifically reduced the expression of the corresponding C/D box small nucleolar RNAs (snoRNAs) SNORD143/144, which guide the rRNA 2′Ome complex at the 28S_Um2402 site. During ZEB1-induced EMT induction/reversion, the levels of both 2′Ome at 28S_Um2402 and SNORD143/144 were dynamically comodulated. Taken together, these data demonstrate that 2′Ome rRNA epitranscriptomics is a novel marker of ZEB1-induced EMT.
2025-02-05 | GSE261572 | GEO
Project description:Throughout most of pregnancy, uterine quiescence is maintained by increased progesterone receptor (PR) transcriptional activity, while spontaneous labor is initiated/facilitated by a concerted series of biochemical events that activate inflammatory pathways and negatively impact PR function. In this study, we uncovered a new regulatory pathway whereby miRNAs serve as hormonally-modulated and conserved mediators of contraction-associated genes in the pregnant uterus from mouse to human. Using miRNA and gene expression microarray analyses of uterine tissues, we identified a conserved family of miRNAs, the miR-200 family, that is highly induced at term in both mice and humans, as well as two coordinately downregulated targets, zinc finger E-box binding homeobox proteins, ZEB1 and ZEB2, which act as transcriptional repressors. We also observed upregulation of the miR-200 family and downregulation of ZEB1 and ZEB2 in two different mouse models of preterm labor. We further demonstrated that ZEB1 is directly upregulated by the action of P4/PR at the ZEB1 promoter. Excitingly, we observed that ZEB1 and ZEB2 inhibit expression of the contraction- associated genes, oxytocin receptor and connexin-43 and block oxytocin-induced contractility in human myometrial cells. Together, these findings implicate the miR-200 family and their targets ZEB1 and ZEB2 as novel progesterone/PR- mediated regulators of uterine quiescence and contractility during pregnancy and labor, and shed new light on the molecular mechanisms involved in preterm birth. RNA was purified from mouse myometrium (miRNeasy kit, Qiagen). miRNA microarray was performed (LC Sciences) on 18 biological replicates of murine myometrium at 15.5 dpc and an equal number of replicates at 18.5 dpc. Gene expression microarray assays were performed (UT Southwestern Medical Center) on the same 36 samples as detailed further in SI Materials and Methods.
2010-10-30 | E-GEOD-25017 | biostudies-arrayexpress
Project description:Throughout most of pregnancy, uterine quiescence is maintained by increased progesterone receptor (PR) transcriptional activity, while spontaneous labor is initiated/facilitated by a concerted series of biochemical events that activate inflammatory pathways and negatively impact PR function. In this study, we uncovered a new regulatory pathway whereby miRNAs serve as hormonally-modulated and conserved mediators of contraction-associated genes in the pregnant uterus from mouse to human. Using miRNA and gene expression microarray analyses of uterine tissues, we identified a conserved family of miRNAs, the miR-200 family, that is highly induced at term in both mice and humans, as well as two coordinately downregulated targets, zinc finger E-box binding homeobox proteins, ZEB1 and ZEB2, which act as transcriptional repressors. We also observed upregulation of the miR-200 family and downregulation of ZEB1 and ZEB2 in two different mouse models of preterm labor. We further demonstrated that ZEB1 is directly upregulated by the action of P4/PR at the ZEB1 promoter. Excitingly, we observed that ZEB1 and ZEB2 inhibit expression of the contraction- associated genes, oxytocin receptor and connexin-43 and block oxytocin-induced contractility in human myometrial cells. Together, these findings implicate the miR-200 family and their targets ZEB1 and ZEB2 as novel progesterone/PR- mediated regulators of uterine quiescence and contractility during pregnancy and labor, and shed new light on the molecular mechanisms involved in preterm birth.
2010-10-30 | GSE25017 | GEO
Project description:In-vitro expansion of functional adult human β-cells is an attractive approach for generating insulin-producing cells for transplantation. However, human islet cell expansion in culture results in loss of β-cell phenotype and epithelial-mesenchymal transition (EMT). This process activates expression of ZEB1 and ZEB2, two members of the zinc-finger homeobox family of E-cadherin repressors, which play key roles in EMT. Downregulation of ZEB1 using shRNA in expanded β-cell-derived (BCD) cells induced mesenchymal-epithelial transition (MET), β-cell gene expression, and proliferation attenuation. In addition, inhibition of ZEB1 expression potentiated redifferentiation induced by a combination of soluble factors, as judged by an improved response to glucose stimulation and a 3-fold increase in the fraction of C-peptide-positive cells to 60% of BCD cells. Furthermore, ZEB1 shRNA led to increased insulin secretion in cells transplanted in vivo. Our findings suggest that the effects of ZEB1 inhibition are mediated by attenuation of the miR-200c target genes SOX6 and SOX2. These findings, which were reproducible in cells derived from multiple human donors, emphasize the key role of ZEB1 in EMT in cultured BCD cells and support the value of ZEB1 inhibition for BCD cell redifferentiation and generation of functional human β-like cells for cell therapy of diabetes.
2015-07-27 | GSE69658 | GEO
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 HCT116 colorectal cancer cells. HCT116 is a cell line that exhibits mesenchymal characteristics, but reverts to an epithelial phenotype upon ZEB1 knock down (Spaderna et al. 2008 Cancer Research). HCT116 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.
2016-06-15 | E-MTAB-3480 | biostudies-arrayexpress
Project description:The zinc finger e-box binding homeobox 1 (ZEB1) transcription factor is a master regulator of the epithelial to mesenchymal transition (EMT), and of the reverse mesenchymal to epithelial transition (MET) processes. ZEB1 plays an integral role in mediating cell state transitions during cell lineage specification, wound healing and disease. EMT/MET are characterized by distinct changes in molecular and cellular phenotype that are generally context-independent. Posterior polymorphous corneal dystrophy (PPCD), associated with ZEB1 insufficiency, provides a new biological context in which to understand and evaluate the classic EMT/MET paradigm. PPCD is characterized by a cadherin-switch and transition to an epithelial-like transcriptomic and cellular phenotype, which we study in a cell-based model of PPCD generated using CRISPR-Cas9-mediated ZEB1 knockout in corneal endothelial cells (CEnCs). Transcriptomic and functional studies support the hypothesis that CEnC undergo an MET-like transition in PPCD, termed endothelial to epithelial transition (EnET), and lead to the conclusion that EnET may be considered a corollary to the classic EMT/MET paradigm.
2019-06-13 | GSE121680 | GEO
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). It is now known that EMT activation is also associated with the maintenance of stem-cell properties (Mani et al, 2008). 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 siRNA mediated loss of ZEB1 in SW480 colorectal cancer cells. SW480 is a cell line that exhibits mesenchymal characteristics, but reverts to an epithelial phenotype upon ZEB1 knock down (Spaderna et al. 2006 Gastroenterology). SW480 cells were transfected with control (GFP) or ZEB1 siRNA. 72 hours after transfection, cells were harvested, total RNA was isolated and hybridized.
2016-06-15 | E-MTAB-3479 | biostudies-arrayexpress
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 Panc1 pancreatic cancer cells. Panc1 is a cell line that exhibits relatively high ZEB1 levels and changes to a more benign phenotype upon ZEB1 knock down (Wellner et al. 2009 Nature Cell Biology). Panc1 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.
2016-06-15 | E-MTAB-3483 | biostudies-arrayexpress
Project description:Zeb1, a zinc finger E-box binding homeobox epithelial-mesenchymal (EMT) transcription factor, confers properties of ‘stemness’, such as self-renewal, in cancer. Yet little is known about the function of Zeb1 in adult stem cells. Here, we used the hematopoietic system, as a well-established paradigm of stem cell biology, to evaluate Zeb1 mediated regulation of adult stem cells. We employed a conditional genetic approach using the Mx1-Cre system to specifically knockout (KO) Zeb1 in adult hematopoietic stem cells (HSCs) and their downstream progeny. Acute genetic deletion of Zeb1 led to rapid onset thymic atrophy and apoptosis driven loss of thymocytes and T cells. A profound cell-autonomous self-renewal defect and multi-lineage differentiation block was observed in Zeb1 KO HSCs. Loss of Zeb1 in HSCs activated transcriptional programs of deregulated HSC maintenance and multi-lineage differentiation genes, and of cell polarity, consisting of cytoskeleton, lipid metabolism/lipid membrane and cell adhesion related genes. Notably, Epithelial cell adhesion molecule (EpCAM) expression was prodigiously upregulated in Zeb1 KO HSCs, which correlated with their enhanced cell survival capacity and diminished differentiation in transplantation. Thus, Zeb1 acts as a crucial transcriptional regulator in hematopoiesis, co-ordinating HSC self-renewal and multi-lineage differentiation fates, in part, via EpCAM repression.
2020-07-02 | GSE153663 | GEO
Project description:Zeb1, a zinc finger E-box binding homeobox epithelial-mesenchymal (EMT) transcription factor, confers properties of ‘stemness’, such as self-renewal, in cancer. Yet little is known about the function of Zeb1 in adult stem cells. Here, we used the hematopoietic system, as a well-established paradigm of stem cell biology, to evaluate Zeb1 mediated regulation of adult stem cells. We employed a conditional genetic approach using the Mx1-Cre system to specifically knockout (KO) Zeb1 in adult hematopoietic stem cells (HSCs) and their downstream progeny. Acute genetic deletion of Zeb1 led to rapid onset thymic atrophy and apoptosis driven loss of thymocytes and T cells. A profound cell-autonomous self-renewal defect and multi-lineage differentiation block was observed in Zeb1 KO HSCs. Loss of Zeb1 in HSCs activated transcriptional programs of deregulated HSC maintenance and multi-lineage differentiation genes, and of cell polarity, consisting of cytoskeleton, lipid metabolism/lipid membrane and cell adhesion related genes. Notably, Epithelial cell adhesion molecule (EpCAM) expression was prodigiously upregulated in Zeb1 KO HSCs, which correlated with their enhanced cell survival capacity and diminished differentiation in transplantation. Thus, Zeb1 acts as a crucial transcriptional regulator in hematopoiesis, co-ordinating HSC self-renewal and multi-lineage differentiation fates, in part, via EpCAM repression.
2020-07-02 | GSE153662 | GEO