Elsevier

Journal of Autoimmunity

Volume 41, March 2013, Pages 92-99
Journal of Autoimmunity

Review
Impaired DNA methylation and its mechanisms in CD4+T cells of systemic lupus erythematosus

https://doi.org/10.1016/j.jaut.2013.01.005Get rights and content

Abstract

Systemic lupus erythematosus (SLE) is a prototypical autoimmune disease characterized by production of autoantibodies against a series of nuclear antigens. Although the exact cause of SLE is still unknown, the influence of environment, which is largely reflected by the epigenetic mechanisms, with DNA methylation changes in particular, are generally considered as key players in the pathogenesis of SLE. As an important post-translational modification, DNA methylation mainly suppresses the expression of relevant genes. Accumulating evidence has indicated that abnormal DNA hypomethylation in T cells is an important epigenetic hallmark in SLE. Apart from those classic methylation-sensitive autoimmunity-related genes in lupus, such as CD11a (ITGAL), Perforin (PRF1), CD70 (TNFSF7), CD40 ligand (TNFSF5) and PP2Acα, the genome-wide methylation pattern has also been explored recently, providing us a more and more full-scale picture of the abnormal status of DNA methylation in SLE. On the other hand, certain miRNAs, RFX1, defective ERK pathway signaling, Gadd45α and DNA hydroxymethylation have been proposed as potential mechanisms leading to DNA hypomethylation in lupus. In this review, we summarize current understanding of T cell DNA methylation changes and the consequently altered gene expressions in lupus, and how they contribute to the development of SLE. Possible mechanisms underlying these aberrancies are also discussed based on the reported literature and our own findings.

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)

  • N.M. Valiante et al.

    Functionally and structurally distinct NK cell receptor repertoires in the peripheral blood of two human donors

    Immunity

    (1997)
  • Y. Liu et al.

    DNA methylation inhibition increases T cell KIR expression through effects on both promoter methylation and transcription factors

    Clin Immunol

    (2009)
  • C. Matache et al.

    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

    (2003)
  • Y.H. Chang et al.

    Elevated circulatory MMP-2 and MMP-9 levels and activities in patients with rheumatoid arthritis and systemic lupus erythematosus

    Clin Biochem

    (2008)
  • B. Cauwe et al.

    Deficiency of gelatinase B/MMP-9 aggravates lpr-induced lymphoproliferation and lupus-like systemic autoimmune disease

    J Autoimmun

    (2011)
  • Y. Thabet et al.

    Altered patterns of epigenetic changes in systemic lupus erythematosus and auto-antibody production: is there a link?

    J Autoimmun

    (2012)
  • A.A. Tveita et al.

    Increased glomerular matrix metalloproteinase activity in murine lupus nephritis

    Kidney Int

    (2008)
  • D.P. Bartel

    MicroRNAs: target recognition and regulatory functions

    Cell

    (2009)
  • B.P. Lewis et al.

    Conserved seed pairing, often flanked by adenosines, indicates that thousands of human genes are microRNA targets

    Cell

    (2005)
  • K. Layer et al.

    Autoimmunity as the consequence of a spontaneous mutation in Rasgrp1

    Immunity

    (2003)
  • M. Zhao et al.

    Epigenetics and SLE:RFX1 downregulation causes CD11a and CD70 overexpression by altering epigenetic modifications in lupus CD4+ T cells

    J Autoimmun

    (2010)
  • F.M. Strickland et al.

    Environmental exposure, estrogen and two X chromosomes are required for disease development in an epigenetic model of lupus

    J Autoimmun

    (2012)
  • Y. Xu et al.

    Tet3 CXXC domain and dioxygenase activity cooperatively regulate key genes for Xenopus eye and neural development

    Cell

    (2012)
  • A.P. Wolffe et al.

    Epigenetics: regulation through repression

    Science

    (1999)
  • M.J. Kaplan et al.

    Demethylation of promoter regulatory elements contributes to perforin overexpression in CD4+ lupus T cells

    J Immunol

    (2004)
  • Q. Lu et al.

    Demethylation of ITGAL (CD11a) regulatory sequences in systemic lupus erythematosus

    Arthritis Rheum

    (2002)
  • Q. Lu et al.

    Demethylation of CD40LG on the inactive X in T cells from women with lupus

    J Immunol

    (2007)
  • K. Oelke et al.

    Overexpression of CD70 and overstimulation of IgG synthesis by lupus T cells and T cells treated with DNA methylation inhibitors

    Arthritis Rheum

    (2004)
  • R. Lister et al.

    Human DNA methylomes at base resolution show widespread epigenomic differences

    Nature

    (2009)
  • A. Bird

    DNA methylation patterns and epigenetic memory

    Genes Dev

    (2002)
  • M. Okano et al.

    Cloning and characterization of a family of novel mammalian DNA (cytosine-5) methyltransferases

    Nat Genet

    (1998)
  • M. Bostick et al.

    UHRF1 plays a role in maintaining DNA methylation in mammalian cells

    Science

    (2007)
  • J. Sharif et al.

    The SRA protein Np95 mediates epigenetic inheritance by recruiting Dnmt1 to methylated DNA

    Nature

    (2007)
  • E. Balada et al.

    DNA methylation and systemic lupus erythematosus

    Ann N Y Acad Sci

    (2007)
  • F. Song et al.

    Association of tissue-specific differentially methylated regions (TDMs) with differential gene expression

    Proc Natl Acad Sci U S A

    (2005)
  • N.P. Blackledge et al.

    CpG island chromatin: a platform for gene regulation

    Epigenetics

    (2011)
  • A.M. Deaton et al.

    CpG islands and the regulation of transcription

    Genes Dev

    (2011)
  • A. Razin et al.

    DNA methylation and gene function

    Science

    (1980)
  • A.C. Bell et al.

    Methylation of a CTCF-dependent boundary controls imprinted expression of the Igf2 gene

    Nature

    (2000)
  • D.N. Mancini et al.

    Site-specific DNA methylation in the neurofibromatosis (NF1) promoter interferes with binding of CREB and SP1 transcription factors

    Oncogene

    (1999)
  • W.G. Zhu et al.

    Methylation of adjacent CpG sites affects Sp1/Sp3 binding and activity in the p21(Cip1) promoter

    Mol Cell Biol

    (2003)
  • O. Bogdanovic et al.

    DNA methylation and methyl-CpG binding proteins: developmental requirements and function

    Chromosoma

    (2009)
  • K.D. Robertson

    DNA methylation and human disease

    Nat Rev Genet

    (2005)
  • B. Richardson et al.

    Evidence for impaired T cell DNA methylation in systemic lupus erythematosus and rheumatoid arthritis

    Arthritis Rheum

    (1990)
  • N. Hogg et al.

    T-cell integrins: more than just sticking points

    J Cell Sci

    (2003)
  • B.C. Richardson et al.

    Phenotypic and functional similarities between 5-azacytidine-treated T cells and a T cell subset in patients with active systemic lupus erythematosus

    Arthritis Rheum

    (1992)
  • B. Richardson et al.

    Lymphocyte function-associated antigen 1 overexpression and T cell autoreactivity

    Arthritis Rheum

    (1994)
  • R. Yung et al.

    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

    (1996)
  • J. Quddus et al.

    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

    (1993)
  • Y. Luo et al.

    Abnormal DNA methylation in T cells from patients with subacute cutaneous lupus erythematosus

    Br J Dermatol

    (2008)
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