IFN-α Suppresses GATA3 Transcription from a Distal Exon and Promotes H3K27 Trimethylation of the CNS-1 Enhancer in Human Th2 Cells

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-alpha/beta) 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-alpha/beta signaling represses the GATA3 gene in human Th2 cells. IFN-alpha/beta 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-alpha/beta 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-alpha/beta signaling, even in the presence of IL-4. Thus, IFN-alpha/beta disrupts the GATA3autoactivation loop and promotes epigenetic silencing of a Th2-specific regulatory region within the GATA3 gene.