Down-regulation of IL-7Ralpha expression in human T cells via DNA methylation.
IL-7 is critical for the development and survival of T cells. Recently, we found two subsets of human CD8+ T cells expressing IL-7Ralpha(high) and IL-7Ralpha(low) with different cell survival responses to IL-7. Although these CD8+ T cell subsets have differential IL-7Ralpha gene expression, the mechanism for this is unknown. DNA methylation is an important gene regulatory mechanism and is associated with the inactivation of gene expression. Thus, we investigated a role for DNA methylation in differentially regulating IL-7Ralpha gene expression in human CD8+ T cells and Jurkat T cells. IL-7Ralpha(high)CD8+ T cells had decreased methylation in the IL-7Ralpha gene promoter compared with IL-7Ralpha(low)CD8+ T cells and Jurkat T cells with low levels of IL-7Ralpha. Treating Jurkat T cells with 5-aza-2'-deoxycytidine, which reduced DNA methylation, increased IL-7Ralpha expression. Plus, the unmethylated IL-7Ralpha gene promoter construct had higher levels of promoter activity than the methylated one as measured by a luciferase reporter assay. These findings suggest that DNA methylation is involved in regulating IL-7Ralpha expression in T cells via affecting IL-7Ralpha gene promoter activity, and that the methylation of this gene promoter could be a potential target for modifying IL-7-mediated T cell development and survival.
Kim
Hang-Rae
HR
Department of Internal Medicine, Section of Rheumatology, Yale University School of Medicine, New Haven, CT 06520, USA.
Hwang
Kyung-A
KA
Kim
Ki-Chan
KC
Kang
Insoo
I
D001374:Azacitidine / Q000031:analogs & derivatives / Q000494:pharmacology; D018414:CD8-Positive T-Lymphocytes; D016207:Cytokines / Q000378:metabolism; D019175:DNA Methylation; D000077209:Decitabine; D015536:Down-Regulation; D005786:Gene Expression Regulation; D006801:Humans; D007156:Immunologic Memory / Q000235:genetics; D019169:Jurkat Cells; D011401:Promoter Regions, Genetic; D020395:Receptors, Interleukin-7 / Q000235:genetics*; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology*
D016207:Cytokines; D020395:Receptors, Interleukin-7; C415350:interleukin-7 receptor, alpha chain; D000077209:Decitabine; D001374:Azacitidine