Epigenetic mechanisms of regulation of FoxP3 expression

Abstract

Review article Epigenetic mechanisms of regulation of Foxp3 expression Girdhari Lal1 and Jonathan S. Bromberg1-4 1Department of Gene and Cell Medicine, 2Department of Surgery, 3Recanati/Miller Transplantation Institute, and 4Immunology Center, Mount Sinai School of Medicine, New York, NY Regulatory T cells play important roles in the control of autoimmunity and mainte- nance of transplantation tolerance. Foxp3, a member of the forkhead/winged-helix family of transcription factors, acts as the master regulator for regulatory T-cell (Treg) development and function. Muta- tion of the Foxp3 gene causes the scurfy phenotype in mouse and IPEX syndrome (immune dysfunction, polyendocrinopa- thy, enteropathy, X-linked syndrome) in humans. Epigenetics is defined by regula- tion of gene expression without altering nucleotide sequence in the genome. Sev- eral epigenetic markers, such as histone acetylation and methylation, and cyto- sine residue methylation in CpG dinucle- otides, have been reported at the Foxp3 locus. In particular, CpG dinucleotides at the Foxp3 locus are methylated in naive CD4
CD25 T cells, activated CD4
T cells, and TGF-–induced adaptive Tregs, whereas they are completely de- methylated in natural Tregs. The DNA methyltransferases DNMT1 and DNMT3b are associated with the Foxp3 locus in CD4
T cells. Methylation of CpG residues represses Foxp3 expression, whereas complete demethylation is required for stable Foxp3 expression. In this review, we discuss how different cis-regulatory elements at the Foxp3 locus are sub- jected to epigenetic modification in dif- ferent subsets of CD4
T cells and regu- late Foxp3 expression, and how these mechanisms can be exploited to gen- erate efficiently large numbers of sup- pressive Tregs for therapeutic purposes. (Blood. 2009;114:3727-3735) Introduction Foxp3, a member of forkhead/winged-helix family of transcription factors acts as a “master” regulator for the development and suppressive function of regulatory T cells (

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