[HTML][HTML] Epigenetic Control of the foxp3 Locus in Regulatory T Cells

S Floess, J Freyer, C Siewert, U Baron, S Olek… - PLoS …, 2007 - journals.plos.org
S Floess, J Freyer, C Siewert, U Baron, S Olek, J Polansky, K Schlawe, HD Chang, T Bopp
PLoS biology, 2007journals.plos.org
Compelling evidence suggests that the transcription factor Foxp3 acts as a master switch
governing the development and function of CD4+ regulatory T cells (Tregs). However,
whether transcriptional control of Foxp3 expression itself contributes to the development of a
stable Treg lineage has thus far not been investigated. We here identified an evolutionarily
conserved region within the foxp3 locus upstream of exon-1 possessing transcriptional
activity. Bisulphite sequencing and chromatin immunoprecipitation revealed complete …
Compelling evidence suggests that the transcription factor Foxp3 acts as a master switch governing the development and function of CD4+ regulatory T cells (Tregs). However, whether transcriptional control of Foxp3 expression itself contributes to the development of a stable Treg lineage has thus far not been investigated. We here identified an evolutionarily conserved region within the foxp3 locus upstream of exon-1 possessing transcriptional activity. Bisulphite sequencing and chromatin immunoprecipitation revealed complete demethylation of CpG motifs as well as histone modifications within the conserved region in ex vivo isolated Foxp3+CD25+CD4+ Tregs, but not in naïve CD25CD4+ T cells. Partial DNA demethylation is already found within developing Foxp3+ thymocytes; however, Tregs induced by TGF-β in vitro display only incomplete demethylation despite high Foxp3 expression. In contrast to natural Tregs, these TGF-β–induced Foxp3+ Tregs lose both Foxp3 expression and suppressive activity upon restimulation in the absence of TGF-β. Our data suggest that expression of Foxp3 must be stabilized by epigenetic modification to allow the development of a permanent suppressor cell lineage, a finding of significant importance for therapeutic applications involving induction or transfer of Tregs and for the understanding of long-term cell lineage decisions.
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