Hypersensitive site 7 of the TH2 locus control region is essential for expressing TH2 cytokine genes and for long-range intrachromosomal interactions
Gap Ryol Lee1, Charalampos G Spilianakis1 & Richard A Flavell1, 2
1 Section of Immunobiology, Yale School of Medicine, New Haven, Connecticut 06520, USA.
2 Howard Hughes Medical Institute, Yale School of Medicine, New Haven, Connecticut 06520, USA.
Correspondence should be addressed to Richard A Flavell
Several regulatory regions are important for the expression of genes encoding T helper type 2 (TH2) cytokines, including TH2-specific DNase I hypersensitivity sites in the TH2 cytokine locus control region. Among these sites, Rad50 hypersensitive site 7 (RHS7) shows rapid TH2-specific demethylation after antigenic stimulation. To investigate the function of RHS7 in TH2 cell differentiation, we have generated RHS7-deficient mice. CD4+ T cells and mast cells showed a notable reduction in TH2 cytokine expression in vitro and TH2 responses in vivo were considerably impaired in RHS7-deficient mice. Deletion of RHS7 did not affect the expression of a linked Rad50 gene, but it did reduce long-range intrachromosomal interactions between the locus control region and promoters of the TH2 cytokine genes. Our findings show that RHS7 is essential for the proper regulation of TH2 cytokine gene expression.