- Transcriptional regulation is a central mechanism in controlling epithelial-to-mesenchymal transition (EMT), orchestrating the complex gene expression changes that allow epithelial cells to acquire mesenchymal properties. This regulation is primarily driven by a core group of EMT-inducing transcription factors (EMT-TFs), including Snail (SNAI1), Slug (SNAI2), Twist1/2, ZEB1, and ZEB2, which repress epithelial gene expression and activate mesenchymal gene programs.
- During EMT, these transcription factors downregulate the expression of epithelial markers, such as E-cadherin (CDH1), occludin, and claudins, which are essential for maintaining tight junctions and cell-cell adhesion. Simultaneously, they upregulate mesenchymal markers like vimentin, N-cadherin, fibronectin, and various matrix metalloproteinases (MMPs) that enhance cell motility, invasiveness, and extracellular matrix remodeling. This coordinated shift in gene expression results in the dissolution of epithelial architecture and the gain of mesenchymal traits such as motility, polarity loss, and resistance to apoptosis.
- The expression and activity of EMT-TFs are regulated by multiple signaling pathways, including TGF-β, Wnt/β-catenin, Notch, Hedgehog, FGF, and NF-κB, which are often activated in developmental, inflammatory, and tumorigenic contexts. These signaling cascades can initiate or reinforce EMT by inducing EMT-TF expression, stabilizing their activity, or promoting their nuclear localization. For instance, TGF-β signaling, through Smad-dependent and Smad-independent pathways, is a potent inducer of Snail and ZEB transcription factors, while Wnt signaling stabilizes β-catenin, which can act as a co-transcriptional activator in EMT.
- In addition to transcriptional control, epigenetic mechanisms—including DNA methylation, histone modifications, and chromatin remodeling—also contribute to EMT regulation by altering the accessibility of EMT-related genes. For example, hypermethylation of the E-cadherin promoter is a well-known mechanism by which EMT-TFs enforce epithelial gene silencing. Furthermore, non-coding RNAs, such as microRNAs (e.g., miR-200 family) and long non-coding RNAs (lncRNAs), modulate EMT by interacting with transcription factors and target mRNAs, adding an additional layer of post-transcriptional control.
- Transcriptional regulation of EMT plays a pivotal role in both physiological and pathological processes. In embryogenesis and organ development, it is essential for tissue patterning and cell differentiation. In contrast, in cancer, transcriptionally driven EMT is associated with tumor progression, invasion, metastasis, and therapeutic resistance. It also contributes to fibrosis, where persistent EMT promotes fibroblast accumulation and excessive ECM deposition, and to chronic inflammation, where EMT-like changes in epithelial cells compromise tissue integrity and immune regulation.
- In summary, transcriptional regulation is the master controller of EMT, integrating extracellular signals and intracellular networks to modulate gene expression profiles that dictate cellular identity and behavior. The activity of EMT transcription factors and the signaling pathways that regulate them are key targets for therapeutic intervention in diseases where EMT plays a pathogenic role.
