IFN-α suppresses GATA3 transcription from a distal exon and promotes H3K27 trimethylation of the CNS-1 enhancer in human Th2 cells

• Published in: The Journal of immunology (1950) 2014-06, Vol.192 (12), p.5687-5694
• Main Authors: Huber, Jonathan P, Gonzales-van Horn, Sarah R, Roybal, Kole T, Gill, Michelle A, Farrar, J David
• Format: Article
• Language: English
• Subjects: Adult; DNA Methylation - genetics; DNA Methylation - immunology; Enhancer Elements, Genetic - immunology; Exons - immunology; Female; GATA3 Transcription Factor - genetics; GATA3 Transcription Factor - immunology; Humans; Interferon-alpha - genetics; Interferon-alpha - immunology; Interferon-beta - genetics; Interferon-beta - immunology; Interleukin-4 - genetics; Interleukin-4 - immunology; Male; Signal Transduction - genetics; Signal Transduction - immunology; Th2 Cells - cytology; Th2 Cells - immunology; Transcription, Genetic - genetics; Transcription, Genetic - immunology
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.1301908

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.