EZH2 Modulates the DNA Methylome and Controls T Cell Adhesion Through Junctional Adhesion Molecule A in Lupus Patients

Objective EZH2 is an epigenetic regulator that mediates H3K27 trimethylation (H3K27me3) and modulates DNA methylation. The aim of this study was to characterize the role of EZH2 in CD4+ T cells in the pathogenesis of systemic lupus erythematosus. Methods EZH2 expression levels were determined in CD4+ T cells isolated from lupus patients and healthy controls. The epigenetic effects of EZH2 overexpression in CD4+ T cells were evaluated using a genome‐wide DNA methylation approach. Gene expression profiles and microRNAs (miRNAs) were assessed by quantitative polymerase chain reaction, while protein expression was examined by Western blotting. A cell adhesion assay was used to assess adhesion of CD4+ T cells to human microvascular endothelial cells. Results EZH2 and H3K27me3 levels were increased in CD4+ T cells from lupus patients compared to healthy controls. T cell production of EZH2 was down‐regulated in the presence of miR‐26a and miR‐101, and levels of both miRNAs were reduced in lupus CD4+ T cells. Overexpression of EZH2 induced in CD4+ T cells resulted in significant DNA methylation changes. Genes involved in leukocyte adhesion and migration, including F11R (which encodes junctional adhesion molecule A [JAM‐A]), became hypomethylated in CD4+ T cells when EZH2 was overexpressed. Overexpression of EZH2 resulted in increases in JAM‐A expression and CD4+ T cell adhesion. Preincubation of EZH2‐transfected CD4+ T cells with neutralizing antibodies against JAM‐A significantly blunted cell adhesion. Similarly, CD4+ T cells from lupus patients overexpressed JAM‐A and adhered significantly more to endothelial cells than to T cells from healthy controls. Blocking JAM‐A or EZH2 significantly reduced the capacity of lupus CD4+ T cells to adhere to endothelial cells. Conclusion The results of this study identify a novel role of EZH2 in T cell adhesion mediated by epigenetic remodeling and up‐regulation of JAM‐A. Blockade of EZH2 or JAM‐A might have therapeutic potential by acting to reduce T cell adhesion, migration, and extravasation in patients with lupus.