ZEB1ZEB2

ZEB1 and ZEB2 are transcription factors belonging to the ZEB (zinc finger E-box-binding) family, also known as ZFHX1A and ZFHX1B. They are studied as closely related paralogs that regulate gene expression during development and in disease.

Structurally, ZEB1 and ZEB2 contain multiple C2H2 zinc finger DNA-binding domains and a homeobox-related domain, enabling interaction with DNA sequences known as E-boxes. They function primarily as transcriptional repressors, recruiting co-repressors and chromatin-modifying enzymes to target gene promoters and enhancers.

In development, ZEB1 and ZEB2 play roles in tissue morphogenesis, including neural crest formation, organ development, and the establishment of epithelial architecture. In adult tissues, they contribute to maintaining homeostasis and are implicated in fibrosis and other pathologies. Their activity is tightly integrated with signaling pathways such as TGF-beta, through SMAD proteins, linking external cues to transcriptional responses.

A central aspect of ZEB1/2 biology is their regulation of epithelial–mesenchymal transition (EMT). By repressing epithelial markers like E-cadherin and activating mesenchymal programs, they promote cellular plasticity, invasion, and, in cancer, metastasis. They operate within regulatory networks that include the microRNA-200 (miR-200) family, which targets ZEB1/2, and in turn is repressed by ZEB1/2, forming a bistable switch controlling epithelial versus mesenchymal states.

Clinically, ZEB1 and ZEB2 are studied as biomarkers of aggressive disease and as potential therapeutic targets to maintain epithelial characteristics and limit metastasis or fibrotic progression.