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J Autoimmun. 2014 Nov;54:127-36. doi: 10.1016/j.jaut.2014.07.002. Epub 2014 Aug 3.

DNA methylation and mRNA and microRNA expression of SLE CD4+ T cells correlate with disease phenotype.

Author information

1
Department of Dermatology, The Second Xiangya Hospital, Central South University, Hunan Key Laboratory of Medical Epigenomics, Changsha, Hunan, China.
2
Beijing Genomics Institute at Shenzhen, Shenzhen, China.
3
Division of Nephrology, Department of Medicine, University of Hong Kong, Queen Mary Hospital, Hong Kong, China.
4
Division of Rheumatology, Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA.
5
Division of Rheumatology, Allergy and Clinical Immunology, University of California, Davis, CA, USA.
6
Beijing Genomics Institute at Shenzhen, Shenzhen, China. Electronic address: lining@genomics.cn.
7
Department of Dermatology, The Second Xiangya Hospital, Central South University, Hunan Key Laboratory of Medical Epigenomics, Changsha, Hunan, China. Electronic address: qianlu5860@gmail.com.

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.

KEYWORDS:

DNA methylation; Epigenetics; Systemic lupus erythematosus; T cells; Transcriptome; microRNA

PMID:
25091625
DOI:
10.1016/j.jaut.2014.07.002
[Indexed for MEDLINE]

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