Transcription factor-dependent chromatin remodeling of Il18r1 during Th1 and Th2 differentiation.
The IL-18Ralpha-chain is expressed on Th1 but not Th2 cells. We have recently shown that Stat4 is an important component of programming the Il18r1 locus (encoding IL-18Ralpha) for maximal expression in Th1 cells. Il18r1 is reciprocally repressed during Th2 development. In this report, we demonstrate the establishment of DH patterns that are distinct among undifferentiated CD4 T, Th1, and Th2 cells. Stat6 is required for the repression of Il18r1 expression and in Stat6-deficient Th2 cultures, mRNA levels, histone acetylation, and H3K4 methylation levels are intermediate between levels observed in Th1 and Th2 cells. Despite the repressive effects of IL-4 during Th2 differentiation, we observed only modest binding of Stat6 to the Il18r1 locus. In contrast, we observed robust GATA-3 binding to a central region of the locus where DNase hypersensitivity sites overlapped with conserved non-coding sequences in Il18r1 introns. Ectopic expression of GATA-3 in differentiated Th1 cells repressed Il18r1 mRNA and surface expression of IL-18Ralpha. These data provide further mechanistic insight into transcription factor-dependent establishment of Th subset-specific patterns of gene expression.
Yu
Qing
Q
Departments of Pediatrics, Herman B. Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
Chang
Hua-Chen
HC
Ahyi
Ayele-Nati N
AN
Kaplan
Mark H
MH
D000818:Animals; D002454:Cell Differentiation; D042002:Chromatin Assembly and Disassembly; D050990:GATA3 Transcription Factor / Q000502:physiology*; D005786:Gene Expression Regulation; D053727:Interleukin-18 Receptor alpha Subunit / Q000235:genetics*; D051379:Mice; D018345:Mice, Knockout; D011485:Protein Binding; D050800:STAT6 Transcription Factor / Q000502:physiology*; D018417:Th1 Cells / Q000166:cytology*; D018418:Th2 Cells / Q000166:cytology*
D050990:GATA3 Transcription Factor; C494748:Gata3 protein, mouse; C508573:Il18r1 protein, mouse; D053727:Interleukin-18 Receptor alpha Subunit; D050800:STAT6 Transcription Factor; C494100:Stat6 protein, mouse