Epigenetic Control of the foxp3 Locus in Regulatory T Cells Export

@article{citeulike:1080288, abstract = {Compelling evidence suggests that the transcription factor Foxp3 acts as a master switch governing the development and function of CD4\&\#43; 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\&\#43;CD25\&\#43;CD4\&\#43; Tregs, but not in na\&\#239;ve CD25\&\#8722;CD4\&\#43; T cells. Partial DNA demethylation is already found within developing Foxp3\&\#43; thymocytes; however, Tregs induced by TGF-\&\#946; in vitro display only incomplete demethylation despite high Foxp3 expression. In contrast to natural Tregs, these TGF-\&\#946;\&\#8211;induced Foxp3\&\#43; Tregs lose both Foxp3 expression and suppressive activity upon restimulation in the absence of TGF-\&\#946;. 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.}, author = {Floess, Stefan and Freyer, Jennifer and Siewert, Christiane and Baron, Udo and Olek, Sven and Polansky, Julia and Schlawe, Kerstin and Chang, Hyun-Dong and Bopp, Tobias and Schmitt, Edgar and Klein-Hessling, Stefan and Serfling, Edgar and Hamann, Alf and Huehn, Jochen}, citeulike-article-id = {1080288}, citeulike-linkout-0 = {http://dx.doi.org/10.1371/journal.pbio.0050038}, day = {1}, doi = {10.1371/journal.pbio.0050038}, journal = {PLoS Biology}, keywords = {mammals, regulation, tf, transcription}, month = {February}, number = {2}, pages = {e38+}, posted-at = {2007-01-31 15:47:41}, priority = {2}, title = {Epigenetic Control of the foxp3 Locus in Regulatory T Cells}, url = {http://dx.doi.org/10.1371/journal.pbio.0050038}, volume = {5}, year = {2007} }

TY - JOUR ID - citeulike:1080288 L3 - citeulike-article-id:1080288 N2 - 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 CD25−CD4+ 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. IS - 2 JF - PLoS Biology TI - Epigenetic Control of the foxp3 Locus in Regulatory T Cells VL - 5 SP - e38 KW - mammals KW - regulation KW - tf KW - transcription AU - Floess, Stefan AU - Freyer, Jennifer AU - Siewert, Christiane AU - Baron, Udo AU - Olek, Sven AU - Polansky, Julia AU - Schlawe, Kerstin AU - Chang, Hyun-Dong AU - Bopp, Tobias AU - Schmitt, Edgar AU - Klein-Hessling, Stefan AU - Serfling, Edgar AU - Hamann, Alf AU - Huehn, Jochen PY - 2007/02/01/ UR - http://dx.doi.org/10.1371/journal.pbio.0050038 ER -