Deletion of EZH2 increases oral epithelial cell stress responses

Enhancer of zeste homolog 2 (EZH2), a member of polycomb repressive complex 2 (PRC2), is expressed in almost all basal stem cells (SCs) of the epithelial lining of the tongue. We previously generated a transgenic mouse model (KcEZH2) containing a tamoxifen (tam) dependent CreER system to selectively knock out (KO) EZH2 (KcEZH2-T) in most tongue basal epithelial SCs. Here, we used this model to assess EZH2 actions in normal tongue epithelia. Genome-wide transcriptomics revealed that signaling pathways associated with stress responses were increased, whereas cell-cycle-related processes and cell proliferation were decreased in KcEZH2-T oral epithelia. Indeed, EZH2 KO increased the expression of EGR1, BTG2, c-Fos, and c-Jun proteins, which are products of immediate-early genes (IEGs) associated with cellular responses during various types of cell stress, and decreased Ki67 protein. Our chromatin immunoprecipitation (ChIP) data in tongue epithelia of wild type mice showed that the chromatin near specific regions of the Egr1, Btg2, and Fos genes displayed H3K27me3 marks, the epigenetic modification catalyzed by EZH2 in canonical PRC2 complex assemblies. We additionally found that Loricrin and E-cadherin proteins were increased in KcEZH2-T vs. KcEZH2 oral epithelia. Thus, our data demonstrate that deletion of EZH2 increases stress-related responses in normal tongue epithelia. As previous studies show that IEGs are increased while cell cycle progression is suppressed in early stages of wound repair, transiently inhibiting EZH2 expression and function warrants further investigation as a hypothetical framework for innovative wound healing approaches.