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Epigenetic modification of the human CCR6 gene is associated with stable CCR6 expression in T cells.
Steinfelder, Svenja Floess, Stefan Engelbert, Dirk Haeringer, Barbara Baron, Udo Rivino, Laura Steckel, Bodo Gruetzkau, Andreas Olek, Sven Geginat, Jens
Steinfelder, Svenja
Floess, Stefan
Engelbert, Dirk
Haeringer, Barbara
Baron, Udo
Rivino, Laura
Steckel, Bodo
Gruetzkau, Andreas
Olek, Sven
Geginat, Jens
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2011-03-10
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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.
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Epigenetic modification of the human CCR6 gene is associated with stable CCR6 expression in T cells. 2011, 117 (10):2839-46 Blood
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en
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1528-0020
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