| Budget Amount *help |
¥3,600,000 (Direct Cost: ¥3,600,000)
Fiscal Year 2000: ¥1,400,000 (Direct Cost: ¥1,400,000)
Fiscal Year 1999: ¥2,200,000 (Direct Cost: ¥2,200,000)
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| Research Abstract |
IL-7 receptor (IL-7R) plays critical roles in lymphocyte development by promoting survival and proliferation and by inducing V (D) J recombination in TCR and Ig loci. To identify the molecular mechanism of the induction of gene rearrangement by IL-7R, we characterized the role of Stat5 in the germline transcription of TCRγ genes. Our results demonstrated that IL-7R-activated Stat5 binds to consensus motifs in 5' regions of Jγ segments and induces germline transcripts. We also found that a constitutively-active form of Stat5 induces germline transcription, restores V-J recombination of TCRγ genes, and partially rescues T cell development from IL-7R-/-T cell precursors, especially in favor of γδ T cells. Therefore, these results revealed a potential role of Stat5 in T cell development, and implied that Stat5 may control the accessibility of the TCRγ locus by the induction of germline transcripts. Next, to identify the molecular mechanism that links the Stat5-induced germline transcription to the accessibility of the TCRγ locus, we characterized the role of transcriptional coactivators and histone acetylation in TCRγ genes. We demonstrated that cytokine stimulation rapidly recruits Stat5 and transcriptional coactivators to the 5'Jγ germline promoter and increases histone acetylation, germline transcription, and accessibility in Ba/F3 cells. We also show that histone acetylation of the TCRγ locus is significantly reduced in IL-7R-deficient thymocyte precursors and that introduction of active Stat5 restores the histone acetylation and accessibility of the TCRγ locus. Therefore, these results suggested that Stat5 controls local accessibility of the Jγ region by recruiting the transcriptional coactivators and inducing histone acetylation. Our study also implied a potential role of Stat5 in the locus-wide accessibility control by the TCRγ enhancer (Eγ).
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