Epigenetic modification of the human CCR6 gene is associated with stable CCR6 expression in T cells

Svenja Steinfelder, Stefan Floess, Dirk Engelbert, Barbara Haeringer, Udo Baron, Laura Rivino, Bodo Steckel, Andreas Gruetzkau, Sven Olek, Jens Geginat, Jochen Huehn, Alf Hamann

Research output: Contribution to journalArticle (Academic Journal)peer-review

Abstract

CCR6 is a chemokine receptor expressed on Th17 cells and regulatory T cells that is induced by T-cell priming with certain cytokines, but how its expression and stability are regulated at the molecular level is largely unknown. Here, we identified and characterized a noncoding region of the human CCR6 locus that displayed unmethylated CpG motifs (differentially methylated region [DMR]) selectively in CCR6(+) lymphocytes. CCR6 expression on circulating CD4(+) T cells was stable on cytokine-induced proliferation but partially down-regulated on T-cell receptor stimulation. However, CCR6 down-regulation was mostly transient, and the DMR within the CCR6 locus remained demethylated. Notably, in vitro induction of CCR6 expression with cytokines in T-cell receptor-activated naive CD4(+) T cells was not associated with a demethylated DMR and resulted in unstable CCR6 expression. Conversely, treatment with the DNA methylation inhibitor 5'-azacytidine induced demethylation of the DMR and led to increased and stable CCR6 expression. Finally, when cloned into a reporter gene plasmid, the DMR displayed transcriptional activity in memory T cells that was suppressed by DNA methylation. In summary, we have identified a noncoding region of the human CCR6 gene with methylation-sensitive transcriptional activity in CCR6(+) T cells that controls stable CCR6 expression via epigenetic mechanisms.

Original languageEnglish
Pages (from-to)2839-46
Number of pages8
JournalBlood
Volume117
Issue number10
DOIs
Publication statusPublished - 10 Mar 2011

Keywords

  • Cell Separation
  • DNA Methylation/genetics
  • Epigenesis, Genetic/genetics
  • Flow Cytometry
  • Gene Expression
  • Gene Expression Regulation/genetics
  • Humans
  • Polymerase Chain Reaction
  • Receptors, CCR6/genetics
  • T-Lymphocytes/metabolism
  • Transfection

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