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.
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.
Authors: Yuxia Zhang; Sarah Kinkel; Jovana Maksimovic; Esther Bandala-Sanchez; Maria C Tanzer; Gaetano Naselli; Jian-Guo Zhang; Yifan Zhan; Andrew M Lew; John Silke; Alicia Oshlack; Marnie E Blewitt; Leonard C Harrison Journal: Blood Date: 2014-06-20 Impact factor: 22.113
Authors: Matlock A Jeffries; Mikhail Dozmorov; Yuhong Tang; Joan T Merrill; Jonathan D Wren; Amr H Sawalha Journal: Epigenetics Date: 2011-05-01 Impact factor: 4.528
Authors: Qiang Shu; Mohammad A Amin; Jeffrey H Ruth; Phillip L Campbell; Alisa E Koch Journal: Arthritis Res Ther Date: 2012-04-25 Impact factor: 5.156
Authors: Soumyaroop Bhattacharya; Jared A Mereness; Andrea M Baran; Ravi S Misra; Derick R Peterson; Rita M Ryan; Anne Marie Reynolds; Gloria S Pryhuber; Thomas J Mariani Journal: Front Immunol Date: 2021-01-21 Impact factor: 7.561