title: Increased 5-hydroxymethylcytosine in CD4(+) T cells in systemic lupus erythematosus.
abstract: One of the major disappointments in autoimmunity has been the relative lack of informative data when genomewide associations (GWAS) have been applied to patients with systemic lupus erythematosus (SLE). Indeed, there is increasing evidence that SLE is characterized by widespread epigenetic changes. 5-Hydroxymethylcytosine (5-hmC) is a newly discovered modified form of cytosine suspected to be an important epigenetic modification in embryonic development, cell differentiation and cancer. DNA methylation dynamics have already been implicated in the pathogenesis of SLE, while little is known about hydroxymethylation in this process. Here, we show an increased 5-hmC level in genomic DNA in CD4(+) T cells of patients with SLE compared with healthy controls, accompanied by the up-regulated expression of the Ten-eleven translocation TET2 and TET3, which can enzymatically convert 5-methylcytosine (5-mC) to 5-hmC. Moreover, we present the differential patterns of DNA hydroxymethylation in genome-wide promoter regions in SLE CD4(+) T cells compared with healthy controls. We identified 2748 genes with increased 5-hmC levels in promoter regions in SLE CD4(+) T cells, which were enriched in critical pathways, including neurotrophin signaling, WNT signaling, MAPK signaling, calcium signaling and the mTOR signaling pathway. Through a combined analysis of differential DNA hydroxymethylation profile and gene expression profile in SLE CD4(+) T cells, we found 131 genes with the increased 5-hmC in promoter regions and up-regulated expression in SLE CD4(+) T cells compared with healthy controls, including selected immune-related genes, i.e. SOCS1, NR2F6 and IL15RA, which were also confirmed by ChIP-qPCR. Furthermore, we demonstrate that CTCF, as a transcription factor, can mediate DNA hydroxymethylation and contribute to overexpression of SOCS1 in CD4(+) T cells through binding to the promoter region of SOCS1. Taken together, our study reveals a critical differential 5-hmC in the genome-wide promoter regions of SLE CD4(+) T cells and provides a novel mechanism that suggests that DNA hydroxymethylation contributes to the aberrant regulation of genes transcription in the pathogenesis of SLE.
authors.affiliation: Department of Dermatology, The Second Xiangya Hospital of Central South University, Hunan Key Laboratory of Medical Epigenomics, Changsha, Hunan, PR China.
authors.forename: Ming
authors.initials: M
authors.lastname: Zhao
authors.affiliation: Department of Dermatology, The Second Xiangya Hospital of Central South University, Hunan Key Laboratory of Medical Epigenomics, Changsha, Hunan, PR China.
authors.forename: Jing
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Dermatology, The Second Xiangya Hospital of Central South University, Hunan Key Laboratory of Medical Epigenomics, Changsha, Hunan, PR China.
authors.forename: Wei
authors.initials: W
authors.lastname: Liao
authors.affiliation: Department of Dermatology, The Second Xiangya Hospital of Central South University, Hunan Key Laboratory of Medical Epigenomics, Changsha, Hunan, PR China.
authors.forename: Duo
authors.initials: D
authors.lastname: Li
authors.affiliation: Department of Dermatology, The Second Xiangya Hospital of Central South University, Hunan Key Laboratory of Medical Epigenomics, Changsha, Hunan, PR China.
authors.forename: Mengying
authors.initials: M
authors.lastname: Li
authors.affiliation: Department of Dermatology, The Second Xiangya Hospital of Central South University, Hunan Key Laboratory of Medical Epigenomics, Changsha, Hunan, PR China.
authors.forename: Haijing
authors.initials: H
authors.lastname: Wu
authors.affiliation: Department of Dermatology, The Second Xiangya Hospital of Central South University, Hunan Key Laboratory of Medical Epigenomics, Changsha, Hunan, PR China.
authors.forename: Yiqun
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Division of Rheumatology, Allergy and Clinical Immunology, University of California, Davis, CA, USA.
authors.forename: M Eric
authors.initials: ME
authors.lastname: Gershwin
authors.affiliation: Department of Dermatology, The Second Xiangya Hospital of Central South University, Hunan Key Laboratory of Medical Epigenomics, Changsha, Hunan, PR China. Electronic address: qianlu5860@gmail.com.
authors.forename: Qianjin
authors.initials: Q
authors.lastname: Lu
mesh_terms: D044503:5-Methylcytosine / Q000031:analogs & derivatives; D000328:Adult; D015551:Autoimmunity; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism*; D016022:Case-Control Studies; D047369:Chromatin Immunoprecipitation; D003596:Cytosine / Q000031:analogs & derivatives* / Q000378:metabolism; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D005260:Female; D015870:Gene Expression; D005786:Gene Expression Regulation; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D008180:Lupus Erythematosus, Systemic / Q000175:diagnosis / Q000209:etiology* / Q000378:metabolism*; D008297:Male; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D012333:RNA, Messenger / Q000235:genetics; D053647:Receptors, Interleukin-15 / Q000235:genetics / Q000378:metabolism; D011987:Receptors, Steroid / Q000235:genetics / Q000378:metabolism; D012097:Repressor Proteins; D012720:Severity of Illness Index; D000071222:Suppressor of Cytokine Signaling 1 Protein / Q000235:genetics / Q000378:metabolism; D055815:Young Adult
chemical_list: C508024:IL15RA protein, human; C075835:NR2F6 protein, human; D012333:RNA, Messenger; D053647:Receptors, Interleukin-15; D011987:Receptors, Steroid; D012097:Repressor Proteins; D000071222:Suppressor of Cytokine Signaling 1 Protein; C011865:5-hydroxymethylcytosine; D044503:5-Methylcytosine; D003596:Cytosine
keywords: CD4(+) T cells; CTCF; Epigenetics; Hydroxymethylation; Methylation; SOCS1; Systemic lupus erythematosus