Abstract

Objectives The peripheral blood T cells epigenetic modification and adhesion capacity alterations are the characteristic of SLE. EZH2 induces proinflammatory epigenetic changes in immune regulation. JAM-A widely involves in cell adhesion. However, the molecular regulation mechanisms between EZH2 and JAM-A in T cells of SLE patients remain undefined. Methods EZH2 and JAM-A expression levels in T cells from SLE patients and healthy controls were evaluated via FCM and RT-qPCR. The regulatory mechanism between miR-26a-5p/EZH2 and JAM-A were investigated via BSP-PCR, ChIP assays, cell adhesion assays in vitro , and intraperitoneal GSK126 administration in MRL/ lpr mice in vivo . Results We found the expression of EZH2 and JAM-A was upregulated in SLE patients’ T cells. Mechanistically, EZH2 epigenetically repressed its target gene DNMT3A, mediated by H3K27me3, which consequently decreased the methylation levels in JAM-A promoter region, resulting in promoting the expression of JAM-A. Subsequently, JAM-A promoted the expression of its functionally relevant target gene Rap1a, a regulator of β1-integrin, involved in T cell adhesion. In addition, we show that both EZH2 and Rap1a are the target genes of miR-26a-5p. Specially, EZH2-mediated H3K27me3 modification in miR-26a-5p promoter region further inhibited the transcription of miR-26a-5p, resulting in the upregulation of EZH2 in T cells of SLE patients, creating a vicious cycle. And intraperitoneal administrating the inhibitor of EZH2 with GSK126 significantly ameliorated the nephritis in MRL/ lpr mice. Conclusion This research reveals a novel epigenetic regulation of JAM-A by EZH2-DNMT3A cascade contributes to T cell adhesion capacity via the activation of Rap1a/β1-integrin in lupus patients.