Stat4 limits DNA methyltransferase recruitment and DNA methylation of the IL-18Ralpha gene during Th1 differentiation.
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-18Ralpha 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-18Ralpha expression, and blocking DNA methylation increases IL-18Ralpha 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.
Yu
Qing
Q
Department of Microbiology and Immunology, Walther Oncology Center, HB Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
Thieu
Vivian T
VT
Kaplan
Mark H
MH
D000818:Animals; D002454:Cell Differentiation / Q000502:physiology*; D047369:Chromatin Immunoprecipitation; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000378:metabolism*; D019175:DNA Methylation; D000090205:DNA Methyltransferase 3A; D005786:Gene Expression Regulation / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D008954:Models, Biological; D053724:Receptors, Interleukin-18 / Q000378:metabolism*; D050797:STAT4 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D018417:Th1 Cells / Q000166:cytology* / Q000378:metabolism
C000715535:Dnmt3a protein, mouse; D053724:Receptors, Interleukin-18; D050797:STAT4 Transcription Factor; C494091:Stat4 protein, mouse; D004248:DNA (Cytosine-5-)-Methyltransferases; D000090205:DNA Methyltransferase 3A