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. (Blood. 2011; 117(10): 2839-2846).
Epigenetic modification of the human CCR6 gene is associated with stable CCR6 expression in T cells / S. Steinfelder, S. Floess, D. Engelbert, B. Haeringer, U. Baron, L. Rivino, B. Steckel, A. Gruetzkau, S. Olek, J. Geginat, J. Huehn, A. Hamann. - In: BLOOD. - ISSN 0006-4971. - 117:10(2011), pp. 2839-2846.
|Titolo:||Epigenetic modification of the human CCR6 gene is associated with stable CCR6 expression in T cells|
|Parole Chiave:||chemokine receptor expression; inflammatory-bowel-disease; DNA methylation analysis; rheumatoid-arthritis; peripheral-blood; foxP3 expression; dendritic cells; T-H-17 cells; TH17 cells; memory|
|Settore Scientifico Disciplinare:||Settore MED/04 - Patologia Generale|
|Data di pubblicazione:||2011|
|Digital Object Identifier (DOI):||http://dx.doi.org/10.1182/blood-2010-06-293027|
|Appare nelle tipologie:||01 - Articolo su periodico|