ReviewImpaired DNA methylation and its mechanisms in CD4+T cells of systemic lupus erythematosus
Highlights
► Aberrant DNA demethylation in T cells is an important epigenetic hallmark in SLE. ► Abnormal miRNAs, RFX1, Gadd45α, TETs and ERK lead to DNA hypomethylation in SLE. ► Hypomethylation of autoimmune-related genes contributes to the development of SLE.
Introduction
Systemic lupus erythematosus (SLE) is a female-predominant heterogeneous systemic autoimmune disease characterized by the production of a variety of antinuclear autoantibodies and multiorgan involvement. Although the etiology of SLE remains unclear, studies have shown that epigenetic factors, especially abnormal DNA methylation patterns, play essential roles in the development of the disease [1]. Epigenetics is the study of heritable changes in gene function that occur without a change in the DNA sequence [2]. The mechanisms of epigenetic regulation include DNA methylation, histone modification and chromatin remodeling, and microRNA interference. As the most prevalent and best-described epigenetic modification, DNA methylation changes are thought to be closely related to the pathogenesis of SLE. Our work has shown that aberrant DNA hypomethylation in some specific genes of CD4+T cells can result in generation of autoreactive T cells and autoantibody production [3], [4], [5], [6]. In this review, we give a thorough summary of the abnormal DNA hypomethylation mechanisms in SLE CD4+T cells and discuss how they are involved in the pathogenesis of this disease.
Section snippets
DNA methylation
DNA methylation typically refers to the biochemical process which involves the addition of a methyl group to the 5′ position of the cytosine pyrimidine ring, mediated by DNA methyltransferases (DNMTs), predominantly at CpG dinucleotides; however, it has been reported that in human embryonic stem cells about 25% of 5-methylcytosine residues (5 mC) occur in a non-CG contexts [7]. As by far the only known epigenetic mark of DNA itself in mammals [8], DNA methylation is established by three DNMTs –
Methylation sensitive genes in lupus T cells
The relationship between abnormal DNA methylation status and SLE was first discovered by Dr. Richardson's group more than twenty years ago when they found that T cells from active lupus patients had a decreased global DNA methylation level (15–20% reduction) [26]. Actually, the group had discovered earlier that 5-azacytidine (5-azaC), an inhibitor of DNA methylation, could induce autoreactivity in cloned CD4+T cells and autoimmune syndrome [27]. The link between DNA hypomethylation, T cell
miRNAs and DNA hypomethylation in lupus
miRNAs are short ∼23 nucleotide noncoding RNAs which act primarily as post-transcriptional regulators, mostly suppressors, through binding to target mRNAs [74]. It is well acknowledged that miRNAs have a widespread impact on expression of protein-coding genes, with approximately over one third of human genes as their conserved targets [75]. Not surprisingly, critical associations between miRNAs and DNA methylation patterns in lupus CD4+T cells have also been reported. Pan et al. [76]
Conclusion and perspectives
Looking back on the more than 20 years of investigations into the involvement of disturbed DNA methylation patterns in the pathogenesis of SLE since the initial discovery that SLE T cells displayed globally hypomethylation and reduced DNMT levels, it has been well recognized that DNA hypomethylation in T cells contributes to the onset and development of drug-induced and idiopathic lupus. An array of genes, sensitive to DNA methylation status in their promoter regions, are overexpressed in T
Acknowledgments
This work was supported by the National Natural Science Foundation of China (No. 30730083, No. 30972745, No. 8110119, No. 30901300 and No. 81220108017), the National Basic Research Program of China (973 Plan) (2009CB825605), the Programs of Science-Technology Commission of Hunan province (2011FJ2007, 2011TP4019-7, 2012WK3046 and 2012TT2015) and the Fundamental Research Funds for the Central Universities.
References (101)
- et al.
Epigenetic regulation and the pathogenesis of systemic lupus erythematosus
Transl Res
(2009) - et al.
DNA methyltransferases Dnmt3a and Dnmt3b are essential for de novo methylation and mammalian development
Cell
(1999) - et al.
Methyl-CpG-binding protein, MeCP2, is a target molecule for maintenance DNA methyltransferase, Dnmt1
J Biol Chem
(2003) - et al.
Targeted mutation of the DNA methyltransferase gene results in embryonic lethality
Cell
(1992) - et al.
Critical DNA binding interactions of the insulator protein CTCF: a small number of zinc fingers mediate strong binding, and a single finger-DNA interaction controls binding at imprinted loci
J Biol Chem
(2007) Effect of an inhibitor of DNA methylation on T cells. II. 5-Azacytidine induces self-reactivity in antigen-specific T4+ cells
Hum Immunol
(1986)- et al.
5-Methylcytosine content of DNA in blood, synovial mononuclear cells and synovial tissue from patients affected by autoimmune rheumatic diseases
J Chromatogr
(1991) - et al.
DNA demethylation of the perforin promoter in CD4(+) T cells from patients with subacute cutaneous lupus erythematosus
J Dermatol Sci
(2009) - et al.
T cell CD40LG gene expression and the production of IgG by autologous B cells in systemic lupus erythematosus
Clin Immunol
(2009) - et al.
Sex-specific differences in the relationship between genetic susceptibility, T cell DNA demethylation and lupus flare severity
J Autoimmun
(2012)
Functionally and structurally distinct NK cell receptor repertoires in the peripheral blood of two human donors
Immunity
DNA methylation inhibition increases T cell KIR expression through effects on both promoter methylation and transcription factors
Clin Immunol
Matrix metalloproteinase-9 and its natural inhibitor TIMP-1 expressed or secreted by peripheral blood mononuclear cells from patients with systemic lupus erythematosus
J Autoimmun
Elevated circulatory MMP-2 and MMP-9 levels and activities in patients with rheumatoid arthritis and systemic lupus erythematosus
Clin Biochem
Deficiency of gelatinase B/MMP-9 aggravates lpr-induced lymphoproliferation and lupus-like systemic autoimmune disease
J Autoimmun
Altered patterns of epigenetic changes in systemic lupus erythematosus and auto-antibody production: is there a link?
J Autoimmun
Increased glomerular matrix metalloproteinase activity in murine lupus nephritis
Kidney Int
MicroRNAs: target recognition and regulatory functions
Cell
Conserved seed pairing, often flanked by adenosines, indicates that thousands of human genes are microRNA targets
Cell
Autoimmunity as the consequence of a spontaneous mutation in Rasgrp1
Immunity
Epigenetics and SLE:RFX1 downregulation causes CD11a and CD70 overexpression by altering epigenetic modifications in lupus CD4+ T cells
J Autoimmun
Environmental exposure, estrogen and two X chromosomes are required for disease development in an epigenetic model of lupus
J Autoimmun
Tet3 CXXC domain and dioxygenase activity cooperatively regulate key genes for Xenopus eye and neural development
Cell
Epigenetics: regulation through repression
Science
Demethylation of promoter regulatory elements contributes to perforin overexpression in CD4+ lupus T cells
J Immunol
Demethylation of ITGAL (CD11a) regulatory sequences in systemic lupus erythematosus
Arthritis Rheum
Demethylation of CD40LG on the inactive X in T cells from women with lupus
J Immunol
Overexpression of CD70 and overstimulation of IgG synthesis by lupus T cells and T cells treated with DNA methylation inhibitors
Arthritis Rheum
Human DNA methylomes at base resolution show widespread epigenomic differences
Nature
DNA methylation patterns and epigenetic memory
Genes Dev
Cloning and characterization of a family of novel mammalian DNA (cytosine-5) methyltransferases
Nat Genet
UHRF1 plays a role in maintaining DNA methylation in mammalian cells
Science
The SRA protein Np95 mediates epigenetic inheritance by recruiting Dnmt1 to methylated DNA
Nature
DNA methylation and systemic lupus erythematosus
Ann N Y Acad Sci
Association of tissue-specific differentially methylated regions (TDMs) with differential gene expression
Proc Natl Acad Sci U S A
CpG island chromatin: a platform for gene regulation
Epigenetics
CpG islands and the regulation of transcription
Genes Dev
DNA methylation and gene function
Science
Methylation of a CTCF-dependent boundary controls imprinted expression of the Igf2 gene
Nature
Site-specific DNA methylation in the neurofibromatosis (NF1) promoter interferes with binding of CREB and SP1 transcription factors
Oncogene
Methylation of adjacent CpG sites affects Sp1/Sp3 binding and activity in the p21(Cip1) promoter
Mol Cell Biol
DNA methylation and methyl-CpG binding proteins: developmental requirements and function
Chromosoma
DNA methylation and human disease
Nat Rev Genet
Evidence for impaired T cell DNA methylation in systemic lupus erythematosus and rheumatoid arthritis
Arthritis Rheum
T-cell integrins: more than just sticking points
J Cell Sci
Phenotypic and functional similarities between 5-azacytidine-treated T cells and a T cell subset in patients with active systemic lupus erythematosus
Arthritis Rheum
Lymphocyte function-associated antigen 1 overexpression and T cell autoreactivity
Arthritis Rheum
Mechanisms of drug-induced lupus. II. T cells overexpressing lymphocyte function-associated antigen 1 become autoreactive and cause a lupuslike disease in syngeneic mice
J Clin Invest
Treating activated CD4+ T cells with either of two distinct DNA methyltransferase inhibitors, 5-azacytidine or procainamide, is sufficient to cause a lupus-like disease in syngeneic mice
J Clin Invest
Abnormal DNA methylation in T cells from patients with subacute cutaneous lupus erythematosus
Br J Dermatol
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