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

J Immunol. 2014 Jun 15;192(12):5687-94. doi: 10.4049/jimmunol.1301908. Epub 2014 May 9.


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.

Publication types

  • Clinical Trial
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • 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*


  • GATA3 Transcription Factor
  • GATA3 protein, human
  • IL4 protein, human
  • Interferon-alpha
  • Interleukin-4
  • Interferon-beta