Stat4 limits DNA methyltransferase recruitment and DNA methylation of the IL-18Rα gene during Th1 differentiation

Qing Yu, Vivian T. Thieu, Mark H. Kaplan

Research output: Contribution to journalArticle

43 Scopus citations

Abstract

Stat4 is required for Th1 development, although how a transiently activated factor generates heritable patterns of gene expression is still unclear. We examined the regulation of IL-18Rα expression to define a mechanism for Stat4-dependent genetic programming of a Th1-associated gene. Although Stat4 binds the Il18r1 promoter following IL-12 stimulation and transiently increases acetylated histones H3 and H4, patterns of histone acetylation alone in Th1 cells may not be sufficient to explain cell-type-specific patterns of gene expression. The level of DNA methylation and recruitment of Dnmt3a to Il18r1 inversely correlate with IL-18Rα expression, and blocking DNA methylation increases IL-18Rα expression. Moreover, there was decreased Il18r1-Dnmt3a association and DNA methylation following transient trichostatin A-induced histone hyperacetylation in Stat4-/-Th1 cultures. Increased association of Dnmt3a and the Dnmt3a cofactor Dnmt3L with the promoters of several Stat4-dependent genes was found in Stat4-/- Th1 cultures, providing a general mechanism for Stat4-dependent gene programming. These data support a mechanism wherein the transient hyperacetylation induced by Stat4 prevents the recruitment of DNA methyltransferases and the subsequent repression of the Il18r1 locus.

Original languageEnglish (US)
Pages (from-to)2052-2060
Number of pages9
JournalEMBO Journal
Volume26
Issue number8
DOIs
StatePublished - Apr 18 2007

Keywords

  • Chromatin
  • Differentiation
  • DNA methylation
  • STAT proteins
  • T helper cell

ASJC Scopus subject areas

  • Genetics
  • Cell Biology

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