title: TGF-beta and IL-6 signals modulate chromatin binding and promoter occupancy by acetylated FOXP3.
abstract: Expression of FOXP3, a potent gene-specific transcriptional repressor, in regulatory T cells is required to suppress autoreactive and alloreactive effector T cell function. Recent studies have shown that FOXP3 is an acetylated protein in a large nuclear complex and FOXP3 actively represses transcription by recruiting enzymatic corepressors, including histone modification enzymes. The mechanism by which extracellular stimuli regulate the FOXP3 complex ensemble is currently unknown. Although TGF-beta is known to induce murine FOXP3(+) Treg cells, TGF-beta in combination with IL-6 attenuates the induction of FOXP3 functional activities. Here we show that TCR stimuli and TGF-beta signals modulate the disposition of FOXP3 into different subnuclear compartments, leading to enhanced chromatin binding in human CD4(+)CD25(+) regulatory T cells. TGF-beta treatment increases the level of acetylated FOXP3 on chromatin and site-specific recruitment of FOXP3 on the human IL-2 promoter. However, the proinflammatory cytokine IL-6 down-regulates FOXP3 binding to chromatin in the presence of TGF-beta. Moreover, histone deacetylation inhibitor (HDACi) treatment abrogates the down-regulating effects of IL-6 and TGF-beta. These studies indicate that HDACi can enhance regulatory T cell function via promoting FOXP3 binding to chromatin even in a proinflammatory cellular microenvironment. Collectively, our data provide a framework of how different signals affect intranuclear redistribution, posttranslational modifications, and chromatin binding patterns of FOXP3.
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA 19104-6082, USA.
authors.forename: Arabinda
authors.initials: A
authors.lastname: Samanta
authors.forename: Bin
authors.initials: B
authors.lastname: Li
authors.forename: Xiaomin
authors.initials: X
authors.lastname: Song
authors.forename: Kathryn
authors.initials: K
authors.lastname: Bembas
authors.forename: Geng
authors.initials: G
authors.lastname: Zhang
authors.forename: Makoto
authors.initials: M
authors.lastname: Katsumata
authors.forename: Sandra J
authors.initials: SJ
authors.lastname: Saouaf
authors.forename: Qiang
authors.initials: Q
authors.lastname: Wang
authors.forename: Wayne W
authors.initials: WW
authors.lastname: Hancock
authors.forename: Yuan
authors.initials: Y
authors.lastname: Shen
authors.forename: Mark I
authors.initials: MI
authors.lastname: Greene
mesh_terms: D000107:Acetylation; D002478:Cells, Cultured; D002843:Chromatin / Q000235:genetics*; D015536:Down-Regulation; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D006801:Humans; D015850:Interleukin-6 / Q000494:pharmacology*; D011401:Promoter Regions, Genetic / Q000235:genetics*; D011485:Protein Binding; D015398:Signal Transduction / Q000187:drug effects* / Q000276:immunology*; D016212:Transforming Growth Factor beta / Q000494:pharmacology*
chemical_list: D002843:Chromatin; D051858:Forkhead Transcription Factors; D015850:Interleukin-6; D016212:Transforming Growth Factor beta
references.citation: Nat Med. 2007 Nov;13(11):1299-307
references.pmid: 17922010
references.citation: Mol Cell Biol. 2001 Jun;21(11):3820-9
references.pmid: 11340173
references.citation: Cell Cycle. 2007 Jun 15;6(12):1432-6
references.pmid: 17592252
references.citation: Cell. 2008 May 30;133(5):775-87
references.pmid: 18510923
references.citation: Nature. 2006 May 11;441(7090):231-4
references.pmid: 16648837
references.citation: J Immunol. 2017 Feb 1;198(3):981-985
references.pmid: 28115586
references.citation: J Immunol. 2007 Apr 1;178(7):4022-6
references.pmid: 17371955
references.citation: Carcinogenesis. 2004 Sep;25(9):1551-7
references.pmid: 15231688
references.citation: Cytokine Growth Factor Rev. 2003 Apr;14(2):85-9
references.pmid: 12651220
references.citation: EMBO J. 1993 Aug;12(8):3237-47
references.pmid: 8344261
references.citation: Trends Immunol. 2005 Jun;26(6):299-304
references.pmid: 15922945
references.citation: J Cell Sci. 2006 Jun 15;119(Pt 12):2457-67
references.pmid: 16720642
references.citation: Nat Immunol. 2005 Apr;6(4):331-7
references.pmid: 15785758
references.citation: Nature. 2006 May 11;441(7090):235-8
references.pmid: 16648838
references.citation: Immunity. 2006 Feb;24(2):179-89
references.pmid: 16473830
references.citation: Mol Cell Biol. 2003 Apr;23(8):2669-79
references.pmid: 12665570
references.citation: Nat Immunol. 2005 Dec;6(12):1219-27
references.pmid: 16244650
references.citation: Nat Immunol. 2003 Apr;4(4):337-42
references.pmid: 12612581
references.citation: Mol Cell Biol. 2006 Jan;26(1):155-68
references.pmid: 16354687
references.citation: Nat Immunol. 2005 Apr;6(4):345-52
references.pmid: 15785760
references.citation: J Immunol. 2007 Feb 15;178(4):2018-27
references.pmid: 17277105
references.citation: Science. 2003 Feb 14;299(5609):1033-6
references.pmid: 12532024
references.citation: J Immunol. 2007 Jun 15;178(12):7667-77
references.pmid: 17548603
references.citation: Eur J Immunol. 2008 Apr;38(4):912-5
references.pmid: 18395858
references.citation: Eur J Immunol. 2004 Nov;34(11):2996-3005
references.pmid: 15468055
references.citation: J Invest Dermatol. 1991 Jan;96(1):31-7
references.pmid: 1987293
references.citation: J Clin Invest. 2005 Nov;115(11):3276-84
references.pmid: 16211090
references.citation: Nat Genet. 2001 Jan;27(1):68-73
references.pmid: 11138001
references.citation: J Biol Chem. 2001 Oct 5;276(40):37672-9
references.pmid: 11483607
references.citation: Immunity. 2008 Apr;28(4):468-76
references.pmid: 18400189
references.citation: Int Immunol. 2007 Jul;19(7):825-35
references.pmid: 17586580
references.citation: Proc Natl Acad Sci U S A. 2007 Jul 17;104(29):12099-104
references.pmid: 17623780
references.citation: Ann N Y Acad Sci. 2001 Sep;941:69-85
references.pmid: 11594584
references.citation: Mol Cell Biol. 2000 Nov;20(22):8602-12
references.pmid: 11046155
references.citation: J Immunol. 2007 Aug 15;179(4):2041-5
references.pmid: 17675459
references.citation: J Exp Med. 2002 Nov 18;196(10):1335-46
references.pmid: 12438424
references.citation: Nature. 2008 May 8;453(7192):236-40
references.pmid: 18368049
references.citation: J Immunol. 2006 Oct 1;177(7):4376-83
references.pmid: 16982872
references.citation: J Biol Chem. 2005 Dec 30;280(52):43100-8
references.pmid: 16219768
references.citation: J Immunol. 2006 May 1;176(9):5240-6
references.pmid: 16621989
references.citation: Nat Immunol. 2008 Jun;9(6):632-40
references.pmid: 18438410
references.citation: Proc Natl Acad Sci U S A. 2007 Mar 13;104(11):4571-6
references.pmid: 17360565
references.citation: Int Immunol. 2004 Dec;16(12):1769-80
references.pmid: 15520045