Drs. S. Zhao, Y. Wang, and Y. Liang contributed equally to this work.
Systemic Lupus Erythematosus
MicroRNA-126 regulates DNA methylation in CD4+ T cells and contributes to systemic lupus erythematosus by targeting DNA methyltransferase 1
Article first published online: 27 APR 2011
Copyright © 2011 by the American College of Rheumatology
Arthritis & Rheumatism
Volume 63, Issue 5, pages 1376–1386, May 2011
How to Cite
Zhao, S., Wang, Y., Liang, Y., Zhao, M., Long, H., Ding, S., Yin, H. and Lu, Q. (2011), MicroRNA-126 regulates DNA methylation in CD4+ T cells and contributes to systemic lupus erythematosus by targeting DNA methyltransferase 1. Arthritis & Rheumatism, 63: 1376–1386. doi: 10.1002/art.30196
- Issue published online: 27 APR 2011
- Article first published online: 27 APR 2011
- Accepted manuscript online: 16 DEC 2010 11:48AM EST
- Manuscript Accepted: 7 DEC 2010
- Manuscript Received: 1 MAR 2010
- National Natural Science Foundation of China. Grant Numbers: 30730083, 30972745
- National Basic Research Program of China. Grant Number: 973 Plan, grant 2009CB825605
To identify microRNA genes with abnormal expression in the CD4+ T cells of patients with systemic lupus erythematosus (SLE) and to determine the role of microRNA-126 (miR-126) in the etiology of SLE.
MicroRNA expression patterns in CD4+ T cells from patients with SLE and healthy control subjects were analyzed by microRNA microarray and stem loop quantitative polymerase chain reaction (qPCR). Luciferase reporter gene assays were performed to identify miR-126 targets. Dnmt1, CD11a, and CD70 messenger RNA and protein levels were determined by real-time qPCR, Western blotting, and flow cytometry. CD11a, CD70, and EGFL7 promoter methylation levels were detected by bisulfite sequencing. IgG levels in T cell–B cell cocultures were determined by enzyme-linked immunosorbent assay.
The expression of 11 microRNA was significantly increased or decreased in CD4+ T cells from patients with SLE relative to that in CD4+ T cells from control subjects. Among these, miR-126 was up-regulated, and its degree of overexpression was inversely correlated with Dnmt1 protein levels. We demonstrated that miR-126 directly inhibits Dnmt1 translation via interaction with its 3′–untranslated region, and that overexpression of miR-126 in CD4+ T cells can significantly reduce Dnmt1 protein levels. The overexpression of miR-126 in CD4+ T cells from healthy donors caused the demethylation and up-regulation of genes encoding CD11a and CD70, thereby causing T cell and B cell hyperactivity. The inhibition of miR-126 in CD4+ T cells from patients with SLE had the opposite effects. Expression of the miR-126 host gene EGFL7 was also up-regulated in CD4+ T cells from patients with SLE, possibly in a hypomethylation-dependent manner.
Our data suggest that miR-126 regulates DNA methylation in CD4+ T cells and contributes to T cell autoreactivity in SLE by directly targeting Dnmt1.