The Histone Variant H2A.Z Is a Master Regulator of the Epithelial-Mesenchymal Transition

Epithelial-mesenchymal transition (EMT) is a profound example of cell plasticity that is crucial for embryonic development and cancer. Although it has long been suspected that chromatin-based mechanisms play a role in this process, no master regulator that can specifically regulate EMT has been identified to date. Here, we show that H2A. Z can coordinate EMT by serving as either an activator or repressor of epithelial or mesenchymal gene expression, respectively. Following induction of EMT by TGF-b, we observed an unexpected loss of H2A. Z across both downregulated epithelial and upregulated mesenchymal promoters. Strikingly, the repression of epithelial gene expression was associated with reduction of H2A. Z upstream of the transcription start site (TSS), while the activation of mesenchymal gene expression was dependent on removal of H2A. Z downstream of the TSS. Therefore, the ability of H2A. Z to regulate EMT is dependent on its position, either upstream or downstream of the TSS.