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

Abstract

CD4+ T helper type 2 (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 interferon (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 have 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 non-coding sequence (CNS-1) upstream of exon 1A. IFN-α/β treatment lead 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.

Maternal obesity alters immune cell frequencies and responses in umbilical cord blood samples

“…Changes in CD4 T subset frequency were accompanied by a significant decrease in IL‐4 production in babies born to overweight mothers. Decreases in IL‐4 production could be linked to the increased plasma levels of IFN‐α2 and IFN‐γ observed in the UCB plasma collected from babies born to obese mothers as IFN‐α2 and IFN‐γ are known to repress IL‐4 expression . We also detected significantly higher numbers of pDCs, which could also be linked to the increased plasma levels of IFN‐α2.…”

DNA methylation of Th2 lineage determination genes at birth is associated with allergic outcomes in childhood

“…For GATA3, 16 CpGs loci, located 2.5 kb upstream of the proximal promoter, were measured (Figure A). This region has been shown to be highly conserved amongst species and contains several Notch and GATA3 binding sites which have been shown to be critical for GATA3 induction during Th2 differentiation . We found that higher methylation of umbilical cord GATA3 CpGs −2211/−2209 bp was associated with a decreased risk of asthma at ages 3 years (cases = 31, controls = 500, median ratio 0.74, P = .006) and at 6‐7 years (cases = 79, controls = 475, median ratio 0.90, P = .048) (Table ).…”

“…This region has been shown to be highly conserved amongst species 33 and contains several Notch and GATA3 binding sites which have been shown to be critical for GATA3 induction during Th2 differentiation. 33,34 We found that higher methylation of umbilical cord GATA3 CpGs À2211/À2209 bp was associated with a decreased risk of asthma at ages 3 years (cases = 31, controls = 500, median ratio 0.74, P = .006) and at 6-7 years (cases = 79, controls = 475, median ratio 0.90, P = .048) ( Table 2). As we found significant associations between asthma at 3 and 6-7 years and GATA3 CpGs, we then used logistic regression to allow adjustment for appropriate covariates.…”

Lower expression of GATA3 and T‐bet correlates with downregulated IL‐10 in severe falciparum malaria

“…Another significant observation in SM was that proinflammatory cytokine IFN‐α showed a moderate positive association with parasitaemia while correlating negatively with GATA3 and IL‐10. A recent finding of special interest in this context is the ability of IFN‐α to selectively repress GATA3 expression in fully committed Th2 cells by histone modifications 8 . Another recent study has shown the Pf genome to contain over 6000 AT‐rich immunostimulatory motifs, which potently induce type I IFN transcription via an unidentified receptor that signals through STING‐mediated pathway 9 .…”