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  3. A novel epigenetic regulation of JAM-A by EZH2-DNMT3A cascade contributes to T cell adhesion via the activation of Rap1a in lupus patients

A novel epigenetic regulation of JAM-A by EZH2-DNMT3A cascade contributes to T cell adhesion via the activation of Rap1a in lupus patients

  • J Transl Autoimmun. 2026 Feb 25:12:100362. doi: 10.1016/j.jtauto.2026.100362.
Lei Ding 1 2,  Huan Gu 1 3,  Yuting Zhong 1,  Hongjian Chen 1,  Wen Lin 1 4,  Qingchun Lei 5,  Liwei Yang 6,  Han Yu 1,  Haoling Song 1,  Xudong Zhang 1,  Min Yu 1,  Xuexiu Chang 7,  Jie Lin 1,  Qinghua Cui 1
Affiliations

Affiliations

  • 1 School of Life Sciences, Yunnan University, Kunming, Yunnan, 650500, PR China.
  • 2 Yunnan International Joint Laboratory of Virology and Immunology, Kunming, Yunnan, 650500, PR China.
  • 3 Department of Infectious Disease and Hepatic Disease, The First People's Hospital of Yunnan Province, The Affiliated Hospital of Kunming University of Science and Technology, Kunming, 650032, Yunnan, PR China.
  • 4 Luoyang Central Hospital Affiliated with Zhengzhou University, Luoyang, Henan, 471000, PR China.
  • 5 Puer People's Hospital, Pu'er, Yunnan, 665000, PR China.
  • 6 Deyang People's Hospital, Deyang, Sichuan, 618099, PR China.
  • 7 Yunnan Collaborative Innovation Center for Plateau Lake Ecology and Environmental Health, College of Agronomy and Life Sciences, Kunming University, Kunming, 650214, PR China.
PMID: 41815940 DOI: 10.1016/j.jtauto.2026.100362
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.

Keywords

Enhancer of Zeste homolog 2 (EZH2); Junctional adhesion molecule-A (JAM-A); Member of the RAS oncogene family (Rap1a); RAP1A; Systemic lupus erythematosus (SLE); T cells.

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