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 epigenetic-based mechanisms play a role in this process, no master epigenetic 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. Specifically, TGFβ-induces the loss of H2A.Z from the promoter regions of both epithelial and mesenchymal genes, but the functional outcomes of this loss are different; epithelial genes become repressed while mesenchymal genes are activated.
We demonstrate that H2A.Z nucleosomes positioned at different locations in a promoter can have different functions, i.e. the -2 nucleosome is involved in gene activation whereas the +1 nucleosome is linked to gene repression. This TGFβ-induced loss of H2A.Z from both epithelial and mesenchymal promoters is mimicked by the inhibition of H2A.Z expression. We suggest that H2A.Z has an important role in maintaining the epithelial state because its removal from certain promoters causes de-differentiation to the mesenchymal state. This is consistent with the finding that H2A.Z appears to regulate the expression of many more epithelial genes compared to the number of mesenchymal genes.
Most interestingly, one key gene that H2A.Z regulates is the TGFβ gene itself. We found that depleting H2A.Z expression induced the TGFβ autocrine loop suggesting that the ability of H2A.Z depletion to promote EMT is a combination of inducing the TGFβ autocrine loop as well as directly regulating important EMT genes. This represents a previously unknown mechanism for the coordinated regulation of gene expression.
(Domaschenz et al., 2017, Cell Reports 21, 943–952)