title: DNA methylation and mRNA and microRNA expression of SLE CD4+ T cells correlate with disease phenotype.
abstract: Systemic lupus erythematosus (SLE) is an autoimmune disease well known for its clinical heterogeneity, and its etiology secondary to a cross-talk involving genetic predisposition and environmental stimuli. Although genome-wide analysis has contributed greatly to our understanding of the genetic basis of SLE, there is increasing evidence for a role of epigenetics. Indeed, recent data have demonstrated that in patients with SLE, there are striking alterations of DNA methylation, histone modifications, and deregulated microRNA expression, the sum of which contribute to over-expression of select autoimmune-related genes and loss of tolerance. To address this issue at the level of clinical phenotype, we performed DNA methylation, mRNA and microRNA expression screening using high-throughput sequencing of purified CD4+ T cells from patients with SLE, compared to age and sex matched controls. In particular, we studied 42 patients with SLE and divided this group into three clinical phenotypes: a) the presence of skin lesions without signs of systemic pathology; b) skin lesions but also chronic renal pathology; and c) skin lesions, chronic renal pathology and polyarticular disease. Interestingly, and as expected, sequencing data revealed changes in DNA methylation in SLE compared to controls. However, and more importantly, although there were common methylation changes found in all groups of SLE compared to controls, there was specific DNA methylation changes that correlated with clinical phenotype. These included changes in the novel key target genes NLRP2, CD300LB and S1PR3, as well as changes in the critical pathways, including the adherens junction and leukocyte transendothelial migration. We also noted that a significant proportion of genes undergoing DNA methylation changes were inversely correlated with gene expression and that miRNA screening revealed the existence of subsets with changes in expression. Integrated analysis of this data highlights specific sets of miRNAs controlled by DNA methylation, and genes that are altered by methylation and targeted by miRNAs. In conclusion, our findings suggest select epigenetic mechanisms that contribute to clinical phenotypes and further shed light on a new venue for basic SLE research.
authors.affiliation: Department of Dermatology, The Second Xiangya Hospital, Central South University, Hunan Key Laboratory of Medical Epigenomics, Changsha, Hunan, China.
authors.forename: Ming
authors.initials: M
authors.lastname: Zhao
authors.affiliation: Beijing Genomics Institute at Shenzhen, Shenzhen, China.
authors.forename: Siyang
authors.initials: S
authors.lastname: Liu
authors.affiliation: Department of Dermatology, The Second Xiangya Hospital, Central South University, Hunan Key Laboratory of Medical Epigenomics, Changsha, Hunan, China.
authors.forename: Shuangyan
authors.initials: S
authors.lastname: Luo
authors.affiliation: Beijing Genomics Institute at Shenzhen, Shenzhen, China.
authors.forename: Honglong
authors.initials: H
authors.lastname: Wu
authors.affiliation: Department of Dermatology, The Second Xiangya Hospital, Central South University, Hunan Key Laboratory of Medical Epigenomics, Changsha, Hunan, China.
authors.forename: Meini
authors.initials: M
authors.lastname: Tang
authors.affiliation: Department of Dermatology, The Second Xiangya Hospital, Central South University, Hunan Key Laboratory of Medical Epigenomics, Changsha, Hunan, China.
authors.forename: Wenjing
authors.initials: W
authors.lastname: Cheng
authors.affiliation: Department of Dermatology, The Second Xiangya Hospital, Central South University, Hunan Key Laboratory of Medical Epigenomics, Changsha, Hunan, China.
authors.forename: Qing
authors.initials: Q
authors.lastname: Zhang
authors.affiliation: Department of Dermatology, The Second Xiangya Hospital, Central South University, Hunan Key Laboratory of Medical Epigenomics, Changsha, Hunan, China.
authors.forename: Peng
authors.initials: P
authors.lastname: Zhang
authors.affiliation: Department of Dermatology, The Second Xiangya Hospital, Central South University, Hunan Key Laboratory of Medical Epigenomics, Changsha, Hunan, China.
authors.forename: Xinhai
authors.initials: X
authors.lastname: Yu
authors.affiliation: Beijing Genomics Institute at Shenzhen, Shenzhen, China.
authors.forename: Yudong
authors.initials: Y
authors.lastname: Xia
authors.affiliation: Beijing Genomics Institute at Shenzhen, Shenzhen, China.
authors.forename: Na
authors.initials: N
authors.lastname: Yi
authors.affiliation: Beijing Genomics Institute at Shenzhen, Shenzhen, China.
authors.forename: Fei
authors.initials: F
authors.lastname: Gao
authors.affiliation: Beijing Genomics Institute at Shenzhen, Shenzhen, China.
authors.forename: Li
authors.initials: L
authors.lastname: Wang
authors.affiliation: Division of Nephrology, Department of Medicine, University of Hong Kong, Queen Mary Hospital, Hong Kong, China.
authors.forename: Susan
authors.initials: S
authors.lastname: Yung
authors.affiliation: Division of Nephrology, Department of Medicine, University of Hong Kong, Queen Mary Hospital, Hong Kong, China.
authors.forename: Tak Mao
authors.initials: TM
authors.lastname: Chan
authors.affiliation: Division of Rheumatology, Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA.
authors.forename: Amr H
authors.initials: AH
authors.lastname: Sawalha
authors.affiliation: Division of Rheumatology, Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA.
authors.forename: Bruce
authors.initials: B
authors.lastname: Richardson
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: Beijing Genomics Institute at Shenzhen, Shenzhen, China. Electronic address: lining@genomics.cn.
authors.forename: Ning
authors.initials: N
authors.lastname: Li
authors.affiliation: Department of Dermatology, The Second Xiangya Hospital, Central South University, Hunan Key Laboratory of Medical Epigenomics, Changsha, Hunan, China. Electronic address: qianlu5860@gmail.com.
authors.forename: Qianjin
authors.initials: Q
authors.lastname: Lu
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000276:immunology; D000328:Adult; D051017:Apoptosis Regulatory Proteins; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000473:pathology; D019175:DNA Methylation / Q000276:immunology*; D005260:Female; D005786:Gene Expression Regulation / Q000276:immunology*; D006801:Humans; D008180:Lupus Erythematosus, Systemic / Q000276:immunology* / Q000473:pathology; D008297:Male; D035683:MicroRNAs / Q000276:immunology*; D012333:RNA, Messenger / Q000276:immunology*; D011971:Receptors, Immunologic / Q000276:immunology; D049349:Receptors, Lysosphingolipid / Q000276:immunology; D000081025:Sphingosine-1-Phosphate Receptors
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D051017:Apoptosis Regulatory Proteins; C519445:CD300LB protein, human; D035683:MicroRNAs; C495732:NLRP2 protein, human; D012333:RNA, Messenger; D011971:Receptors, Immunologic; D049349:Receptors, Lysosphingolipid; D000081025:Sphingosine-1-Phosphate Receptors; C577483:sphingosine-1-phosphate receptor-3, human
keywords: DNA methylation; Epigenetics; Systemic lupus erythematosus; T cells; Transcriptome; microRNA