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

Content Provider	PubMed Central
Author	Huber, Jonathan P. Horn, Sarah R. Gonzales-van Roybal, Kole T. Gill, Michelle A. Farrar, J. David
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.
Related Links	http://dx.doi.org/10.4049/jimmunol.1301908
Ending Page	5694
Page Count	8
Starting Page	5687
File Format	PDF
ISSN	00221767
e-ISSN	15506606
Journal	Journal of immunology (Baltimore, Md. : 1950)
Issue Number	12
Volume Number	192
Language	English
Publisher Date	2014-06-15
Access Restriction	Open
Subject Keyword	Medicine(all) Research in Higher Education
Content Type	Text
Resource Type	Article
Subject	Immunology and Allergy Immunology

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