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

Jonathan P. Huber, Sarah R. Gonzales-Van Horn, Kole T. Roybal, Michelle A. Gill, J. David Farrar

Research output: Contribution to journalArticle

21 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)5687-5694
Number of pages8
JournalJournal of Immunology
Volume192
Issue number12
DOIs
StatePublished - Jun 15 2014

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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