Epigenetic mechanisms of regulation of Foxp3 expression.
Regulatory T cells play important roles in the control of autoimmunity and maintenance 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. Mutation of the Foxp3 gene causes the scurfy phenotype in mouse and IPEX syndrome (immune dysfunction, polyendocrinopathy, enteropathy, X-linked syndrome) in humans. Epigenetics is defined by regulation of gene expression without altering nucleotide sequence in the genome. Several epigenetic markers, such as histone acetylation and methylation, and cytosine residue methylation in CpG dinucleotides, 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-beta-induced adaptive Tregs, whereas they are completely demethylated 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 subjected to epigenetic modification in different subsets of CD4+ T cells and regulate Foxp3 expression, and how these mechanisms can be exploited to generate efficiently large numbers of suppressive Tregs for therapeutic purposes.
Lal
Girdhari
G
Department of Gene and Cell Medicine, Mount Sinai School of Medicine, New York, NY 10029-6574, USA.
Bromberg
Jonathan S
JS
D000818:Animals; D015551:Autoimmunity / Q000235:genetics; D018899:CpG Islands / Q000235:genetics / Q000276:immunology; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D019175:DNA Methylation / Q000235:genetics / Q000276:immunology; D044127:Epigenesis, Genetic; D051858:Forkhead Transcription Factors / Q000096:biosynthesis* / Q000235:genetics / Q000276:immunology; D040181:Genetic Diseases, X-Linked / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D006801:Humans; D007108:Immune Tolerance / Q000235:genetics; D008213:Lymphocyte Activation / Q000235:genetics / Q000276:immunology; D051379:Mice; D009154:Mutation; D016884:Polyendocrinopathies, Autoimmune / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D000097584:DNA Methyltransferase 3B
D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases; D051858:Forkhead Transcription Factors; D016212:Transforming Growth Factor beta; D000097584:DNA Methyltransferase 3B; C418974:FOXP3 protein, human; C498833:Foxp3 protein, mouse; C000619380:DNMT1 protein, human; C000619381:Dnmt1 protein, mouse