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Transcription (co)factor regulatory landscape of EMT [mRNA-seq]

ABSTRACT: To investigate the transcriptional remodelling during EMT, we transfected normal murine mammary gland epithelial cells during a 4d TGFbeta treatment individually with siRNA against 46 transcription (co)factors or with 13 mature miRNA, all factors that blocked EMT in a phenotypic microscopy-based EMT screen upon RNAi . As a control, cells were transfected with siRNA/miRNA control followed by 4d TGFbeta treatment (mesenchymal control) or were left untreated (epithelial control). miRNA-sequencing together with mRNA-sequencing of these EMT perturbations in combination with transcription factor binding and miRNA target prediction enabled us to build an interaction map between these EMT factors.

ORGANISM(S): Mus musculus

PROVIDER: GSE115374 | GEO | 2021/04/06

REPOSITORIES: GEO

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Project description:Transforming growth factor beta-1 (TGFbeta) is a tumor suppressor during the initial stage of tumorigenesis, but it can switch to a tumor promoter during neoplastic progression. Ionizing radiation (IR), both a carcinogen and a therapeutic agent, induces TGFbeta activation in vivo. We now show that IR sensitizes human mammary epithelial cells (HMEC) to undergo TGFbeta-mediated epithelial to mesenchymal transition (EMT). Non-malignant HMEC (MCF10A, HMT3522 S1 and 184v) were irradiated with 2 Gy shortly after attachment in monolayer culture, or treated with a low concentration of TGFbeta (0.4 ng/ml), or double-treated. All double-treated (IR+TGFbeta) HMEC underwent a morphological shift from cuboidal to spindle-shaped. This phenotype was accompanied by decreased expression of epithelial markers E-cadherin, beta-catenin and ZO-1, remodeling of the actin cytoskeleton, and increased expression of mesenchymal markers N-cadherin, fibronectin and vimentin. Furthermore, double-treatment increased cell motility, promoted invasion and disrupted acinar morphogenesis of cells subsequently plated in Matrigel. Neither radiation nor TGFbeta alone elicited EMT, even though IR increased chronic TGFbeta signaling and activity. Gene expression profiling revealed that double treated cells exhibit a specific 10-gene signature associated with Erk/MAPK signaling. We hypothesized that IR-induced MAPK activation primes non-malignant HMEC to undergo TGFbeta-mediated EMT. Consistent with this, Erk phosphorylation were transiently induced by irradiation, persisted in irradiated cells treated with TGFbeta, and treatment with U0126, a Mek inhibitor, blocked the EMT phenotype. Together, these data demonstrate that the interactions between radiation-induced signaling pathways elicit heritable phenotypes that could contribute to neoplastic progression. Keywords: response to ionizing radiation, response to transforming growth factor-beta, nonmalignant human mammary epithelial MCF10A cells, epithelial to mesenchymal transition

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Transcription (co)factor regulatory landscape of EMT [mRNA-seq]

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