title: Genome-wide DNA methylation analysis identifies hypomethylated genes regulated by FOXP3 in human regulatory T cells.
abstract: Regulatory T cells (Treg) prevent the emergence of autoimmune disease. Prototypic natural Treg (nTreg) can be reliably identified by demethylation at the Forkhead-box P3 (FOXP3) locus. To explore the methylation landscape of nTreg, we analyzed genome-wide methylation in human naive nTreg (rTreg) and conventional naive CD4(+) T cells (Naive). We detected 2315 differentially methylated cytosine-guanosine dinucleotides (CpGs) between these 2 cell types, many of which clustered into 127 regions of differential methylation (RDMs). Activation changed the methylation status of 466 CpGs and 18 RDMs in Naive but did not alter DNA methylation in rTreg. Gene-set testing of the 127 RDMs showed that promoter methylation and gene expression were reciprocally related. RDMs were enriched for putative FOXP3-binding motifs. Moreover, CpGs within known FOXP3-binding regions in the genome were hypomethylated. In support of the view that methylation limits access of FOXP3 to its DNA targets, we showed that increased expression of the immune suppressive receptor T-cell immunoglobulin and immunoreceptor tyrosine-based inhibitory motif domain (TIGIT), which delineated Treg from activated effector T cells, was associated with hypomethylation and FOXP3 binding at the TIGIT locus. Differential methylation analysis provides insight into previously undefined human Treg signature genes and their mode of regulation.
authors: The Walter and Eliza Hall Institute of Medical Research, Parkville, Australia;
authors: Yuxia
authors: Y
authors: Zhang
authors: Jovana
authors: J
authors: Maksimovic
authors: Gaetano
authors: G
authors: Naselli
authors: Junyan
authors: J
authors: Qian
authors: Michael
authors: M
authors: Chopin
authors: Marnie E
authors: ME
authors: Blewitt
authors: Alicia
authors: A
authors: Oshlack
authors: Leonard C
authors: LC
authors: Harrison
mesh_terms: D020816:Amino Acid Motifs; D018899:CpG Islands; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D051858:Forkhead Transcription Factors / Q000235:genetics* / Q000378:metabolism; D005786:Gene Expression Regulation; D015894:Genome, Human; D006801:Humans; D016130:Immunophenotyping; D008297:Male; D020411:Oligonucleotide Array Sequence Analysis / Q000379:methods; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D050378:T-Lymphocytes, Regulatory / Q000166:cytology*
chemical_list: C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors
references: Nat Genet. 2009 Feb;41(2):178-186
references: 19151715
references: BMC Mol Biol. 2012 May 29;13:16
references: 22642378
references: Immunity. 2009 Jan 16;30(1):155-67
references: 19144320
references: J Immunol. 2010 Jun 15;184(12):6773-81
references: 20483747
references: Genome Res. 2009 Jul;19(7):1165-74
references: 19494038
references: Epigenomics. 2011 Dec;3(6):771-84
references: 22126295
references: J Immunol. 2011 Feb 1;186(3):1338-42
references: 21199897
references: Int J Epidemiol. 2012 Feb;41(1):200-9
references: 22422453
references: Genome Res. 2008 May;18(5):780-90
references: 18316654
references: Genome Biol. 2006;7(7):R54
references: 16836768
references: Nature. 2007 Feb 22;445(7130):936-40
references: 17237761
references: Science. 2003 Feb 14;299(5609):1057-61
references: 12522256
references: J Exp Med. 2007 Jul 9;204(7):1543-51
references: 17591856
references: Nat Immunol. 2010 Jan;11(1):7-13
references: 20016504
references: Genome Biol. 2009;10(3):R25
references: 19261174
references: Curr Opin Endocrinol Diabetes Obes. 2012 Aug;19(4):271-8
references: 22732485
references: J Mol Med (Berl). 2010 Oct;88(10):1029-40
references: 20574810
references: J Immunol. 2012 Apr 15;188(8):3869-75
references: 22427644
references: Nat Protoc. 2009;4(1):44-57
references: 19131956
references: J Exp Med. 2006 Jul 10;203(7):1693-700
references: 16818676
references: J Immunol. 2010 Jul 15;185(2):1071-81
references: 20554955
references: Biostatistics. 2011 Apr;12(2):197-210
references: 20858772
references: Nucleic Acids Res. 2011 Oct;39(18):7946-60
references: 21729870
references: Eur J Immunol. 2008 Jun;38(6):1654-63
references: 18493985
references: Nat Immunol. 2003 Apr;4(4):330-6
references: 12612578
references: PLoS One. 2011;6(8):e24226
references: 21918685
references: Nat Immunol. 2009 Jan;10(1):48-57
references: 19011627
references: Nature. 2010 Feb 11;463(7282):808-12
references: 20072126
references: Nat Rev Immunol. 2010 Jul;10(7):490-500
references: 20559327
references: Immunity. 2012 Nov 16;37(5):785-99
references: 23123060
references: Proc Int Conf Intell Syst Mol Biol. 1994;2:28-36
references: 7584402
references: J Immunol. 2007 Jan 1;178(1):280-90
references: 17182565
references: PLoS Biol. 2007 Feb;5(2):e38
references: 17298177
references: Cell. 2012 Sep 28;151(1):153-66
references: 23021222
references: Immunity. 2007 Nov;27(5):786-800
references: 18024188
references: Nature. 2007 Feb 22;445(7130):931-5
references: 17237765
references: Nature. 2009 Nov 19;462(7271):315-22
references: 19829295
references: J Mol Biol. 2004 Apr 23;338(2):207-15
references: 15066426
references: Genome Biol. 2008;9(9):R137
references: 18798982
references: BMC Bioinformatics. 2010 Nov 30;11:587
references: 21118553
references: Nat Genet. 2003 Mar;33 Suppl:245-54
references: 12610534
references: J Autoimmun. 2012 Feb;38(1):49-58
references: 22264504
references: Nucleic Acids Res. 2009 Jan;37(1):1-13
references: 19033363
references: J Exp Med. 2006 Jul 10;203(7):1701-11
references: 16818678
references: Eur J Immunol. 2007 Sep;37(9):2378-89
references: 17694575
references: J Immunol. 2010 Apr 1;184(7):3433-41
references: 20181882
references: Nat Genet. 2011 Jun 26;43(8):768-75
references: 21706001
references: J Immunol. 2011 Apr 1;186(7):3918-26
references: 21368230
references: Nat Genet. 2006 Dec;38(12):1378-85
references: 17072317
references: Genome Biol. 2012 Jun 15;13(6):R44
references: 22703947
references: Int Immunol. 2008 Aug;20(8):1041-55
references: 18567616
references: Immunity. 2009 Jun 19;30(6):899-911
references: 19464196