Dataset Information

Epigenetic regulation of epithelial-mesenchymal transition: focusing on hypoxia and TGF-? signaling.

ABSTRACT: Epithelial-mesenchymal transition (EMT) is an important process triggered during cancer metastasis. Regulation of EMT is mostly initiated by outside signalling, including TGF-?, growth factors, Notch ligand, Wnt, and hypoxia. Many signalling pathways have been delineated to explain the molecular mechanisms of EMT. In this review, we will focus on the epigenetic regulation of two critical EMT signalling pathways: hypoxia and TGF-?. For hypoxia, hypoxia-induced EMT is mediated by the interplay between chromatin modifiers histone deacetylase 3 (HDAC3) and WDR5 coupled with the presence of histone 3 lysine 4 acetylation (H3K4Ac) mark that labels the promoter regions of various traditional EMT marker genes (e.g. CDH1, VIM). Recently identified new hypoxia-induced EMT markers belong to transcription factors (e.g. SMO, GLI1) that mediate EMT themselves. For TGF-?-induced ???, global chromatin changes, removal of a histone variant (H2A.Z), and new chromatin modifiers (e.g. UTX, Rad21, PRMT5, RbBP5, etc) are identified to be crucial for the regulation of both EMT transcription factors (EMT-TFs) and EMT markers (EMT-Ms). The epigenetic mechanisms utilized in these two pathways may serve as good model systems for other signalling pathways and also provide new potential therapeutic targets.

SUBMITTER: Lin YT

PROVIDER: S-EPMC7050137 | biostudies-literature | 2020 Mar

REPOSITORIES: biostudies-literature

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Epigenetic regulation of epithelial-mesenchymal transition: focusing on hypoxia and TGF-β signaling.

Lin Yueh-Te YT Wu Kou-Juey KJ

Journal of biomedical science 20200302 1

Epithelial-mesenchymal transition (EMT) is an important process triggered during cancer metastasis. Regulation of EMT is mostly initiated by outside signalling, including TGF-β, growth factors, Notch ligand, Wnt, and hypoxia. Many signalling pathways have been delineated to explain the molecular mechanisms of EMT. In this review, we will focus on the epigenetic regulation of two critical EMT signalling pathways: hypoxia and TGF-β. For hypoxia, hypoxia-induced EMT is mediated by the interplay bet ...[more]

PMID: 32114978

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Project description:BackgroundThe epithelial-mesenchymal transition (EMT) is a de-differentiation process required for wound healing and development. In tumors of epithelial origin aberrant induction of EMT contributes to cancer progression and metastasis. Studies have begun to implicate epigenetic reprogramming in EMT; however, the relationship between reprogramming and the coordination of cellular processes is largely unexplored. We have previously developed a system to study EMT in a canonical non-small cell lung cancer (NSCLC) model. In this system we have shown that the induction of EMT results in constitutive NF-κB activity. We hypothesized a role for chromatin remodeling in the sustained deregulation of cellular signaling pathways.ResultsWe mapped sixteen histone modifications and two variants for epithelial and mesenchymal states. Combinatorial patterns of epigenetic changes were quantified at gene and enhancer loci. We found a distinct chromatin signature among genes in well-established EMT pathways. Strikingly, these genes are only a small minority of those that are differentially expressed. At putative enhancers of genes with the 'EMT-signature' we observed highly coordinated epigenetic activation or repression. Furthermore, enhancers that are activated are bound by a set of transcription factors that is distinct from those that bind repressed enhancers. Upregulated genes with the 'EMT-signature' are upstream regulators of NF-κB, but are also bound by NF-κB at their promoters and enhancers. These results suggest a chromatin-mediated positive feedback as a likely mechanism for sustained NF-κB activation.ConclusionsThere is highly specific epigenetic regulation at genes and enhancers across several pathways critical to EMT. The sites of these changes in chromatin state implicate several inducible transcription factors with critical roles in EMT (NF-κB, AP-1 and MYC) as targets of this reprogramming. Furthermore, we find evidence that suggests that these transcription factors are in chromatin-mediated transcriptional feedback loops that regulate critical EMT genes. In sum, we establish an important link between chromatin remodeling and shifts in cellular reprogramming.

Dataset Information

Epigenetic regulation of epithelial-mesenchymal transition: focusing on hypoxia and TGF-? signaling.

Publications

Epigenetic regulation of epithelial-mesenchymal transition: focusing on hypoxia and TGF-β signaling.

Similar Datasets

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