title: A multiply redundant genetic switch 'locks in' the transcriptional signature of regulatory T cells.
abstract: The transcription factor Foxp3 participates dominantly in the specification and function of Foxp3(+)CD4(+) regulatory T cells (T(reg) cells) but is neither strictly necessary nor sufficient to determine the characteristic T(reg) cell signature. Here we used computational network inference and experimental testing to assess the contribution of other transcription factors to this. Enforced expression of Helios or Xbp1 elicited distinct signatures, but Eos, IRF4, Satb1, Lef1 and GATA-1 elicited exactly the same outcome, acting in synergy with Foxp3 to activate expression of most of the T(reg) cell signature, including key transcription factors, and enhancing occupancy by Foxp3 at its genomic targets. Conversely, the T(reg) cell signature was robust after inactivation of any single cofactor. A redundant genetic switch thus 'locked in' the T(reg) cell phenotype, a model that would account for several aspects of T(reg) cell physiology, differentiation and stability.
authors.affiliation: Division of Immunology, Department of Microbiology and Immunobiology, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Wenxian
authors.initials: W
authors.lastname: Fu
authors.forename: Ayla
authors.initials: A
authors.lastname: Ergun
authors.forename: Ting
authors.initials: T
authors.lastname: Lu
authors.forename: Jonathan A
authors.initials: JA
authors.lastname: Hill
authors.forename: Sokol
authors.initials: S
authors.lastname: Haxhinasto
authors.forename: Marlys S
authors.initials: MS
authors.lastname: Fassett
authors.forename: Roi
authors.initials: R
authors.lastname: Gazit
authors.forename: Stanley
authors.initials: S
authors.lastname: Adoro
authors.forename: Laurie
authors.initials: L
authors.lastname: Glimcher
authors.forename: Susan
authors.initials: S
authors.lastname: Chan
authors.forename: Philippe
authors.initials: P
authors.lastname: Kastner
authors.forename: Derrick
authors.initials: D
authors.lastname: Rossi
authors.forename: James J
authors.initials: JJ
authors.lastname: Collins
authors.forename: Diane
authors.initials: D
authors.lastname: Mathis
authors.forename: Christophe
authors.initials: C
authors.lastname: Benoist
mesh_terms: D000818:Animals; D015704:CD4 Antigens / Q000096:biosynthesis; D002454:Cell Differentiation; D019295:Computational Biology; D004268:DNA-Binding Proteins / Q000096:biosynthesis / Q000235:genetics; D051858:Forkhead Transcription Factors / Q000235:genetics; D050982:GATA1 Transcription Factor / Q000235:genetics; D006801:Humans; D051740:Ikaros Transcription Factor / Q000096:biosynthesis / Q000235:genetics; D050835:Interferon Regulatory Factors / Q000235:genetics; D008213:Lymphocyte Activation; D051821:Lymphoid Enhancer-Binding Factor 1 / Q000235:genetics; D036961:Matrix Attachment Region Binding Proteins / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D000071701:Regulatory Factor X Transcription Factors; D012697:Serine Endopeptidases / Q000235:genetics; D050378:T-Lymphocytes, Regulatory / Q000166:cytology / Q000276:immunology* / Q000378:metabolism*; D014157:Transcription Factors / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic; D000071717:X-Box Binding Protein 1; D000099218:Interferon Regulatory Factor-4
chemical_list: D015704:CD4 Antigens; D004268:DNA-Binding Proteins; D051858:Forkhead Transcription Factors; D050982:GATA1 Transcription Factor; D051740:Ikaros Transcription Factor; D050835:Interferon Regulatory Factors; D051821:Lymphoid Enhancer-Binding Factor 1; D036961:Matrix Attachment Region Binding Proteins; D000071701:Regulatory Factor X Transcription Factors; D012697:Serine Endopeptidases; D014157:Transcription Factors; D000071717:X-Box Binding Protein 1; D000099218:Interferon Regulatory Factor-4; C418974:FOXP3 protein, human; C494688:GATA1 protein, human; C111431:IKZF2 protein, human; C497573:LEF1 protein, human; C076189:SATB1 protein, human; C000605543:XBP1 protein, human; C000605544:Xbp1 protein, mouse; C477245:EOS serine protease, human