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Temporal and Spatial Changes of Histone 3 K4 Dimethylation at the IFN- Gene during Th1 and Th2 Cell Differentiation¹

Heli K. Hamalainen-Laanaya^*, James J. Kobie^*, Chawnshang Chang and Wei-ping Zeng^2,*,

^* David Smith Center for Vaccine Biology and Immunology, Aab Institute for Biomedical Sciences, Department of Microbiology and Immunology, Department of Pathology and Laboratory Medicine, University of Rochester School of Medicine and Dentistry, Rochester, NY 14642

Covalent modification of nucleosomal histones is an important mechanism for cytokine gene regulation in Th1 and Th2 cells. In this study, we analyzed the kinetics of histone H3 K4 dimethylation (H3K4me2) of the IFN- gene. Minimal levels of H3K4me2 were found in naive CD4 T cells. After 5 days of differentiation, H3K4me2 levels were elevated in both Th1 and Th2 cells at the –5.3 kb, the promoter, the intronic DNase I hypersensitive sites, and 3' distal sites including the +9.5 kb and +16 kb sites. Th1 cells maintained high levels of H3K4me2 after longer time of culture. However, in Th2 cells after 14 days, high levels of H3K4me2 were detected only at the –5.3 kb and the promoter, whereas H3K4me2 was lost at the 3' distal sites and greatly diminished at the DNase I hypersensitive sites. After 28 days, Th2 cells lose H3K4me2 at all sites. Unlike the long-term primary Th2 cells, the Th2 clone D10 showed strong H3K4me2 at the IFN- gene with distinctly high levels at the 3' distal sites. CD4 T cells transgenic for Hlx or infected with T-bet-expressing retrovirus produced IFN- and retained high levels of H3K4me2 even after differentiated under Th2 polarizing conditions, suggesting positive roles of these two factors in maintaining high levels of H3K4me2 at the IFN- gene.

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¹ This work is supported by National Institutes of Health Grants AI47263, AI53745, and a Senior Research Award from Crohn’s and Colitis Foundation of America (to W.Z.).

² Address correspondence and reprint requests to Dr. Wei-ping Zeng, Department of Pathology and Laboratory Medicine, University of Rochester School of Medicine and Dentistry, Box 626, 601 Elmwood Avenue, Rochester, NY 14642. E-mail address: weiping_zheng{at}urmc.rochester.edu

³ Abbreviations used in this paper: CNS, conserved noncoding sequences; DHS, DNase I hypersensitivities; H3K4, histone H3 lysine 4; H3K27, histone H3 lysine 27; ChIP, chromatin immunoprecipitation.