Increased 5-hydroxymethylcytosine in CD4+ T cells in systemic lupus erythematosus

Ming Zhao, Jing Wang, Wei Liao, Duo Li, Mengying Li, Haijing Wu, Yiqun Zhang, M. Eric Gershwin, Qianjin Lu

Research output: Contribution to journalArticle

35 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)64-73
Number of pages10
JournalJournal of Autoimmunity
Volume69
DOIs
StatePublished - May 1 2016

Fingerprint

Systemic Lupus Erythematosus
T-Lymphocytes
Genetic Promoter Regions
DNA
Epigenomics
Genes
5-hydroxymethylcytosine
Genome
5-Methylcytosine
Critical Pathways
Calcium Signaling
Cytosine
Nerve Growth Factors
DNA Methylation
Autoimmunity
Transcriptome
Embryonic Development
Cell Differentiation
Transcription Factors

Keywords

  • CD4 T cells
  • CTCF
  • Epigenetics
  • Hydroxymethylation
  • Methylation
  • SOCS1
  • Systemic lupus erythematosus

ASJC Scopus subject areas

  • Immunology
  • Immunology and Allergy

Cite this

Increased 5-hydroxymethylcytosine in CD4+ T cells in systemic lupus erythematosus. / Zhao, Ming; Wang, Jing; Liao, Wei; Li, Duo; Li, Mengying; Wu, Haijing; Zhang, Yiqun; Gershwin, M. Eric; Lu, Qianjin.

In: Journal of Autoimmunity, Vol. 69, 01.05.2016, p. 64-73.

Research output: Contribution to journalArticle

Zhao, Ming ; Wang, Jing ; Liao, Wei ; Li, Duo ; Li, Mengying ; Wu, Haijing ; Zhang, Yiqun ; Gershwin, M. Eric ; Lu, Qianjin. / Increased 5-hydroxymethylcytosine in CD4+ T cells in systemic lupus erythematosus. In: Journal of Autoimmunity. 2016 ; Vol. 69. pp. 64-73.
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