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

Qing Yu, Vivian T Thieu, Mark H Kaplan

Author Affiliations

  1. Qing Yu1,2,
  2. Vivian T Thieu1,2 and
  3. Mark H Kaplan*,1,2
  1. 1 Departments of Microbiology and Immunology, and Pediatrics, Walther Oncology Center, HB Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN, USA
  2. 2 Walther Cancer Institute, Indianapolis, IN, USA
  1. *Corresponding author. Departments of Pediatrics and, Microbiology and Immunology, HB Wells Center for Pediatric Research, Indiana University School of Medicine, 702 Barnhill Dr, RI 2600, Indianapolis, IN 46202, USA. Tel.: +1 317 278 3696; Fax: +1 317 274 5378; E-mail: mkaplan2{at}iupui.edu
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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.

  • Received September 27, 2006.
  • Accepted February 22, 2007.
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