title: Oct-1 regulates IL-17 expression by directing interchromosomal associations in conjunction with CTCF in T cells.
abstract: Interchromosomal associations can regulate gene expression, but little is known about the molecular basis of such associations. In response to antigen stimulation, naive T cells can differentiate into Th1, Th2, and Th17 cells expressing IFN-γ, IL-4, and IL-17, respectively. We previously reported that in naive T cells, the IFN-γ locus is associated with the Th2 cytokine locus. Here we show that the Th2 locus additionally associates with the IL-17 locus. This association requires a DNase I hypersensitive region (RHS6) at the Th2 locus. RHS6 and the IL-17 promoter both bear Oct-1 binding sites. Deletion of either of these sites or Oct-1 gene impairs the association. Oct-1 and CTCF bind their cognate sites cooperatively, and CTCF deficiency similarly impairs the association. Finally, defects in the association lead to enhanced IL-17 induction. Collectively, our data indicate Th17 lineage differentiation is restrained by the Th2 locus via interchromosomal associations organized by Oct-1 and CTCF.
authors.affiliation: Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520, USA; Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, CT 06520, USA.
authors.forename: Lark Kyun
authors.initials: LK
authors.lastname: Kim
authors.affiliation: Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520, USA.
authors.forename: Enric
authors.initials: E
authors.lastname: Esplugues
authors.affiliation: Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520, USA; Department of Genetics, Yale University School of Medicine, New Haven, CT 06520, USA.
authors.forename: Cornelia E
authors.initials: CE
authors.lastname: Zorca
authors.affiliation: Department of Pathology, Yale University School of Medicine, New Haven, CT 06520, USA.
authors.forename: Fabio
authors.initials: F
authors.lastname: Parisi
authors.affiliation: Department of Pathology, Yale University School of Medicine, New Haven, CT 06520, USA.
authors.forename: Yuval
authors.initials: Y
authors.lastname: Kluger
authors.affiliation: Department of Genetics, Yale University School of Medicine, New Haven, CT 06520, USA.
authors.forename: Tae Hoon
authors.initials: TH
authors.lastname: Kim
authors.affiliation: Department of Cell Biology and Genetics, Erasmus MC, 3000 CA Rotterdam, the Netherlands.
authors.forename: Niels J
authors.initials: NJ
authors.lastname: Galjart
authors.affiliation: Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520, USA; Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, CT 06520, USA. Electronic address: richard.flavell@yale.edu.
authors.forename: Richard A
authors.initials: RA
authors.lastname: Flavell
mesh_terms: D000818:Animals; D001665:Binding Sites; D000076246:CCCTC-Binding Factor; D002454:Cell Differentiation; D019070:Cell Lineage; D002478:Cells, Cultured; D033481:Chromosomes, Mammalian; D003850:Deoxyribonuclease I / Q000378:metabolism; D005786:Gene Expression Regulation; D017930:Genes, Reporter; D056426:Genetic Loci; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D020381:Interleukin-17 / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D050811:Octamer Transcription Factor-1 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D017384:Sequence Deletion; D058504:Th17 Cells / Q000276:immunology / Q000378:metabolism*; D018418:Th2 Cells / Q000276:immunology / Q000378:metabolism*; D013997:Time Factors
chemical_list: D000076246:CCCTC-Binding Factor; C000619698:Ctcf protein, mouse; C098680:Il17a protein, mouse; D020381:Interleukin-17; D050811:Octamer Transcription Factor-1; C494166:Pou2f1 protein, mouse; D012097:Repressor Proteins; D049452:Green Fluorescent Proteins; D003850:Deoxyribonuclease I