Sip1ZEB2

Sip1ZEB2 (commonly written ZEB2 or SIP1) is a zinc finger transcription factor encoded by the ZFHX1B gene in vertebrates. It belongs to the ZEB family of E-box-binding homeobox proteins and contains multiple zinc-finger clusters, a homeodomain-like region, a Smad-interacting domain and a CtBP corepressor-binding motif. These features enable ZEB2 to bind DNA, interact with TGF-β/BMP-activated SMAD proteins, and recruit chromatin-modifying cofactors to regulate gene expression.

Functionally, ZEB2 acts primarily as a transcriptional repressor of epithelial genes, most notably E-cadherin, and is a central regulator of epithelial–mesenchymal transition (EMT). It plays critical roles during embryonic development, including neural crest cell specification, migration and differentiation, as well as neural and craniofacial development. ZEB2 integrates extracellular signals from TGF-β/BMP pathways to coordinate cell fate and morphogenetic programs.

Clinically, heterozygous loss-of-function variants in ZEB2 cause Mowat-Wilson syndrome, a multisystem developmental disorder characterized by intellectual disability, distinctive facial features, congenital heart defects and Hirschsprung disease. Dysregulated ZEB2 expression is also implicated in cancer progression and metastasis, where overexpression correlates with increased invasiveness and poor prognosis in several tumor types. ZEB2 is subject to regulation by microRNAs (notably the miR-200 family) and participates in feedback circuits that control plasticity between epithelial and mesenchymal states. Studies in model organisms have shown that complete loss of ZEB2 disrupts neural crest development and is often embryonic lethal.