Abstract
Aberrant CD11a overexpression in CD4+ T cells induces T cell auto-reactivity, which is an important factor for systemic lupus erythematosus (SLE) pathogenesis. Although many studies have focused on CD11a epigenetic regulation, little is known about histone methylation. JMJD3, as a histone demethylase, is capable of specifically removing the trimethyl group from the H3K27 lysine residue, triggering target gene activation. Here, we examined the expression and function of JMJD3 in CD4+ T cells from SLE patients. Significantly decreased H3K27me3 levels and increased JMJD3 binding were detected within the ITGAL (CD11a) promoter locus in SLE CD4+ T cells compared with those in healthy CD4+ T cells. Moreover, overexpressing JMJD3 through the transfection of pcDNA3.1-JMJD3 into healthy donor CD4+ T cells increased JMJD3 enrichment and decreased H3K27me3 enrichment within the ITGAL (CD11a) promoter and up-regulated CD11a expression, leading to T and B cell hyperactivity. Inhibition of JMJD3 via JMJD3-siRNA in SLE CD4+ T cells showed the opposite effects. These results demonstrated that histone demethylase JMJD3 regulates CD11a expression in lupus T cells by affecting the H3K27me3 levels in the ITGAL (CD11a) promoter region, and JMJD3 might thereby serve as a potential therapeutic target for SLE.
Highlights
Systemic lupus erythematosus (SLE) is a multifactorial autoimmune connective tissue disease characterized by aberrant lymphocyte auto-reactivity and excess autoantibody production, leading to inflammation and tissue damage in multiple systems
Inhibition of JMJD3 via JMJD3-siRNA in systemic lupus erythematosus (SLE) CD4+ T cells showed the opposite effects. These results demonstrated that histone demethylase JMJD3 regulates CD11a expression in lupus T cells by affecting the H3K27me3 levels in the ITGAL (CD11a) promoter region, and JMJD3 might thereby serve as a potential therapeutic target for SLE
Decreased H3K27me3 enrichment and increased JMJD3 binding at the CD11a promoter in SLE CD4+ T cells
Summary
Systemic lupus erythematosus (SLE) is a multifactorial autoimmune connective tissue disease characterized by aberrant lymphocyte auto-reactivity and excess autoantibody production, leading to inflammation and tissue damage in multiple systems. Previous studies have identified more than 60 susceptibility genes associated with lupus, demonstrating the critical role of genetics in lupus autoimmunity [3, 4]. Numerous studies have shown that epigenetic alterations triggering T lymphocyte hyperactivation lead to lupus and lupus-like diseases [7,8,9,10]. Previous studies have demonstrated that DNA hypomethylation and histone hyperacetylation of the CD11a promoter region contribute to the overexpression of this protein in SLE CD4+ T cells [7, 16]. The mechanisms responsible for aberrant CD11a overexpression in lupus are not fully understood
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