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Synthetic epigenetic reprogramming of mesenchymal to epithelial states using the CRISPR/dCas9 platform in triple negative breast cancer [RNA-seq]

ABSTRACT: Epithelial-mesenchymal transition (EMT) is a reversible transcriptional program subverted by cancer cells to drive cancer progression. Transcription factor ZEB1 is a master regulator of EMT, driving disease recurrence in poor outcome triple negative breast cancer (TNBC). Here, we silence ZEB1 in TNBC models by CRISPR-mediated epigenetic editing, resulting in nearly complete repression of ZEB1 in vivo, accompanied by long-lasting tumor inhibition. Integrated transcriptomic and epigenetic profiling identified a ZEB1-dependent gene-signature associated with transcriptional up-regulation, promoter DNA demethylation and enhanced chromatin accessibility in core cell adhesion loci, demonstrating epigenetic reprogramming towards a more epithelial state. Epigenetic shifts induced by ZEB1-silencing are enriched in a subset of human breast tumors, illuminating a clinically-relevant hybrid-like state. Thus, the synthetic epi-silencing of ZEB1 induces stable “lock-in” epigenetic reprogramming of mesenchymal tumors associated with a distinct epigenetic landscape. We outline approaches to stably reprogram EMT for targeting poor outcome breast cancers driven by oncogenic transcription factors.

ORGANISM(S): Homo sapiens

PROVIDER: GSE210274 | GEO | 2023/04/17

REPOSITORIES: GEO

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Synthetic epigenetic reprogramming of mesenchymal to epithelial states using the CRISPR/dCas9 platform in triple negative breast cancer [ChIP-seq]

Project description:Epithelial-mesenchymal transition (EMT) is a reversible transcriptional program subverted by cancer cells to drive cancer progression. Transcription factor ZEB1 is a master regulator of EMT, driving disease recurrence in poor outcome triple negative breast cancer (TNBC). Here, we silence ZEB1 in TNBC models by CRISPR-mediated epigenetic editing, resulting in nearly complete repression of ZEB1 in vivo, accompanied by long-lasting tumor inhibition. Integrated transcriptomic and epigenetic profiling identified a ZEB1-dependent gene-signature associated with transcriptional up-regulation, promoter DNA demethylation and enhanced chromatin accessibility in core cell adhesion loci, demonstrating epigenetic reprogramming towards a more epithelial state. Epigenetic shifts induced by ZEB1-silencing are enriched in a subset of human breast tumors, illuminating a clinically-relevant hybrid-like state. Thus, the synthetic epi-silencing of ZEB1 induces stable “lock-in” epigenetic reprogramming of mesenchymal tumors associated with a distinct epigenetic landscape. We outline approaches to stably reprogram EMT for targeting poor outcome breast cancers driven by oncogenic transcription factors.

2023-04-17 | GSE210275 | GEO

Synthetic epigenetic reprogramming of mesenchymal to epithelial states using the CRISPR/dCas9 platform in triple negative breast cancer [ATAC-seq]

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BAG3 suppresses ciliogenesis by regulating levels of OFD1

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2021-06-21 | PXD024802 | Pride

Hypoxia promotes stem cell phenotypes and poor prognosis through epigenetic regulation of DICER [MCF7]

Project description:MicroRNAs are small regulatory RNAs that post-transcriptionally control gene expression. Reduced expression of DICER, the enzyme involved in microRNA processing, is frequently observed in cancer and is associated with poor clinical outcome in various malignancies. Yet the underlying mechanisms are not well understood. Here, we identify tumor hypoxia as a regulator of DICER expression in large cohorts of breast cancer patients. We show that DICER expression is suppressed by hypoxia through an epigenetic mechanism that involves inhibition of oxygen-dependent H3K27me3 demethylases KDM6A/B and results in silencing of the DICER promoter. Subsequently, reduced miRNA processing leads to derepression of the miR-200 target ZEB1, stimulates the epithelial to mesenchymal transition and ultimately results in the acquisition of stem cell phenotypes in human mammary epithelial cells. Our study uncovers a previously unknown relationship between oxygen-sensitive epigenetic regulators, miRNA biogenesis and tumor stem cell phenotypes that may underlie poor outcome in breast cancer. miRNA profiling of MCF7 cells in normal or hypoxic conditions or after DICER knockdown in MCF7 cells.

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Hypoxia promotes stem cell phenotypes and poor prognosis through epigenetic regulation of DICER [HMLER]

Project description:MicroRNAs are small regulatory RNAs that post-transcriptionally control gene expression. Reduced expression of DICER, the enzyme involved in microRNA processing, is frequently observed in cancer and is associated with poor clinical outcome in various malignancies. Yet the underlying mechanisms are not well understood. Here, we identify tumor hypoxia as a regulator of DICER expression in large cohorts of breast cancer patients. We show that DICER expression is suppressed by hypoxia through an epigenetic mechanism that involves inhibition of oxygen-dependent H3K27me3 demethylases KDM6A/B and results in silencing of the DICER promoter. Subsequently, reduced miRNA processing leads to derepression of the miR-200 target ZEB1, stimulates the epithelial to mesenchymal transition and ultimately results in the acquisition of stem cell phenotypes in human mammary epithelial cells. Our study uncovers a previously unknown relationship between oxygen-sensitive epigenetic regulators, miRNA biogenesis and tumor stem cell phenotypes that may underlie poor outcome in breast cancer. A total of 12 samples were analyzed. For each condition tested, 3 independent experiments were carried out (biological repicates).

2014-09-30 | E-GEOD-61721 | biostudies-arrayexpress

Single cell analysis of MCF7-V breast carcinoma cell line stably expressing a doxycyline-inducible construct to express ZEB1 in presence of dxycycline.

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2022-03-14 | GSE173491 | GEO

Zeb1 and Snail1 engage miR-200f transcriptional and epigenetic regulation during EMT

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

RAS-induced transformation of mammary epithelial cells relies on ZEB1-dependent cellular reprogramming through a paracrine process

Project description:The distinct frequency of activation of the RAS/MAPK signaling pathway in human cancers suggests a context-dependent cellular state of vulnerability to RAS transformation. While uncommon in breast cancers, oncogenic activation of this pathway is frequent in claudin-low (CL) tumors, a subtype of breast malignancies enriched in features of epithelial-mesenchymal transition (EMT), suggesting an interplay between RAS activation and EMT. Using inducible models of human mammary epithelial cells, we show that RAS-mediated transformation relies upon cellular reprogramming governed by the EMT-inducing transcription factor ZEB1. The path to ZEB1 induction involves a paracrine process: cells entering a senescent state following RAS induction release proinflammatory cytokines, notably IL-6 and IL1 which promote ZEB1 expression and activity in neighboring cells, thereby fostering their malignant transformation. Collectively, our findings unveil a previously unprecedented role for senescence in bridging RAS activation and EMT over the course of malignant transformation of human mammary epithelial cells.

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WDR5 regulates EMT and metastasis in breast cancer by activating TGFB pathway [RNA-seq PDX]

Project description:The core subunit of the COMPASS-like complex, WD Repeat Domain 5 (WDR5) has a prominent role in reprogramming and Epithelial-to-Mesenchymal transition (EMT) in different tumor types. Our evidences support a model in which WDR5 is prominent for EMT and metastasis dissemination in breast cancer patient-derived xenografts and cell lines. Moreover, WDR5 silencing abrogates TGFB pathway activation and reverts mesenchymal into epithelial phenotype, by inhibiting transcription of main master regulators of EMT (CDH2, TWIST1, SNAI1, SNAI2 and ZEB1). Our data suggest that WDR5 inhibition may be a successful approach to prevent progression of metastatic BC.

2019-12-17 | GSE113288 | GEO

WDR5 regulates EMT and metastasis in breast cancer by activating TGFB pathway [RNA-seq CCL]

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