Abstract
Background: Defective ERK1 activity may regulate the DNA hypomethylation in T cells of lupus mice. Aims: To investigate the function of ERK1 in regulating DNA hypomethylation and explore the potential molecular mechanisms involved in lupus mice. Methods: CD4+T cells were isolated from MRL/lpr and BALB/c mice, activated in vitro in the presence or absence of 5-azacytidine (5-Aza) (a DNA methyltransferase inhibitor)/U0126 (a selective inhibitor of the ERK signaling pathway) respectively. The positive rate of CD4+T cell was measured by flow cytometry, and expression levels of CD70, ERK1, DNA transferase 1 (DNMT1) were estimated by RT-PCR and Western blot. The methylated DNA is detected using the Capture and Detection antibodies, then quantified colorimetrically. Results: The expression level of p-ERK1 in MRL/lpr mice was significantly lower than healthy control (P<0.05); Meanwhile, down regulation of DNMT1 and DNA hypomethylation were found in MRL/lpr mice T cells. In contrary, the expression levels of CD70 increased when compared with healthy control (P<0.05). The same changes were seen in healthy CD4+T cells treated with U0126. Conclusions: DNA hypomethylation regulating mechanisms in lupus T cells were associated with ERK1 signal pathway. U0126 could inhibit ERK1 signal transduction pathway in normal T cells, and induce DNA hypomethylation by regulating the expression of methylation sensitive gene CD70.
Highlights
DNA methylation of eukaryotic chromosome is a regulatory way of gene expression
Mitogen-activated protein kinases (MAPKs) signal pathway play a key role in extracellular signals inducted nucleus response, and ERK pathway is an important member of the family of MAPKs [2, 17]
ERK pathway is an important member of the family of MAPKs which play a key role in extracellular signals, and the expression level of phosphorylated ERKl and ERK1 were abnormal in many autoimmune diseases
Summary
DNA methylation of eukaryotic chromosome is a regulatory way of gene expression. In the process of cell growth and differentiation, the role of DNA methylation is to regulate specific gene expression and the mechanism constitutes epigenetic in gene expression. As a way of regulating the gene expression, DNA methylation play an important role in the immune disorder and tumorigenesis. A growing number of studies show that hypomethylation of CD4+T lymphocytes play a key role in the development of SLE, and abnormal epigenetic regulation mechanism in lupus T lymphocytes may be associated with ERK1 signal pathways. Results: The expression level of p-ERK1 in MRL/lpr mice was significantly lower than healthy control (P
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