title: IFN-α suppresses GATA3 transcription from a distal exon and promotes H3K27 trimethylation of the CNS-1 enhancer in human Th2 cells.
abstract: CD4(+) Th2 development is regulated by the zinc finger transcription factor GATA3. Once induced by acute priming signals, such as IL-4, GATA3 poises the Th2 cytokine locus for rapid activation and establishes a positive-feedback loop that maintains elevated GATA3 expression. Type I IFN (IFN-α/β) inhibits Th2 cells by blocking the expression of GATA3 during Th2 development and in fully committed Th2 cells. In this study, we uncovered a unique mechanism by which IFN-α/β signaling represses the GATA3 gene in human Th2 cells. IFN-α/β suppressed expression of GATA3 mRNA that was transcribed from an alternative distal upstream exon (1A). This suppression was not mediated through DNA methylation, but rather by histone modifications localized to a conserved noncoding sequence (CNS-1) upstream of exon 1A. IFN-α/β treatment led to a closed conformation of CNS-1, as assessed by DNase I hypersensitivity, along with enhanced accumulation of H3K27me3 mark at this CNS region, which correlated with increased density of total nucleosomes at this putative enhancer. Consequently, accessibility of CNS-1 to GATA3 DNA binding activity was reduced in response to IFN-α/β signaling, even in the presence of IL-4. Thus, IFN-α/β disrupts the GATA3-autoactivation loop and promotes epigenetic silencing of a Th2-specific regulatory region within the GATA3 gene.
authors.affiliation: Department of Immunology, University of Texas Southwestern Medical Center, Dallas, TX 75390; and.
authors.forename: Jonathan P
authors.initials: JP
authors.lastname: Huber
authors.affiliation: Department of Immunology, University of Texas Southwestern Medical Center, Dallas, TX 75390; and.
authors.forename: Sarah R
authors.initials: SR
authors.lastname: Gonzales-van Horn
authors.affiliation: Department of Immunology, University of Texas Southwestern Medical Center, Dallas, TX 75390; and.
authors.forename: Kole T
authors.initials: KT
authors.lastname: Roybal
authors.affiliation: Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX 75390.
authors.forename: Michelle A
authors.initials: MA
authors.lastname: Gill
authors.affiliation: Department of Immunology, University of Texas Southwestern Medical Center, Dallas, TX 75390; and David.Farrar@UTSouthwestern.edu.
authors.forename: J David
authors.initials: JD
authors.lastname: Farrar
mesh_terms: D000328:Adult; D019175:DNA Methylation / Q000235:genetics / Q000276:immunology*; D004742:Enhancer Elements, Genetic / Q000276:immunology*; D005091:Exons / Q000276:immunology; D005260:Female; D050990:GATA3 Transcription Factor / Q000235:genetics / Q000276:immunology*; D006801:Humans; D016898:Interferon-alpha / Q000235:genetics / Q000276:immunology*; D016899:Interferon-beta / Q000235:genetics / Q000276:immunology; D015847:Interleukin-4 / Q000235:genetics / Q000276:immunology; D008297:Male; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology*; D018418:Th2 Cells / Q000166:cytology / Q000276:immunology*; D014158:Transcription, Genetic / Q000235:genetics / Q000276:immunology*
chemical_list: D050990:GATA3 Transcription Factor; C494749:GATA3 protein, human; C508598:IL4 protein, human; D016898:Interferon-alpha; D015847:Interleukin-4; D016899:Interferon-beta