depletion of c-rel from cytokine gene promoters is required for chromatin reassembly and termination of gene responses to t cell activation损耗从细胞因子基因染色质重组的需要启动子和终止的基因对t细胞活化的反应.pdfVIP

Depletion of c-Rel from Cytokine Gene Promoters Is Required for Chromatin Reassembly and Termination of Gene Responses to T Cell Activation 1 1¤a 1¤b 1 2 Fiona S. Poke , William R. Upcher , Owen R. Sprod , Arabella Young , Kate H. Brettingham-Moore , Adele F. Holloway1* 1 Menzies Research Institute Tasmania, University of Tasmania, Hobart, Tasmania, Australia, 2 School of Medicine, University of Tasmania, Hobart, Tasmania, Australia Abstract The role of the Nuclear Factor kB (NF-kB) transcription factor family in T cell function has been well described. The c-Rel family member is of particular importance in initiating T cell responses to antigen and regulating activation of inflammatory cytokine genes, including the Interleukin-2 (IL-2) and Granulocyte macrophage colony stimulating factor (GM-CSF) genes. c- Rel is required for chromatin remodeling of these gene promoters, which involves depletion of histones from the promoters in response to T cell activating signals. These chromatin remodeling events precede transcriptional activation of the genes. The subsequent down-regulation of cytokine gene expression is important in the termination of an immune response and here we examine this process at the murine GM-CSF and IL-2 genes. We show that the cytokine mRNA levels rapidly return to basal levels following stimulus removal and this is associated with reassembly of histones onto the promoter. Histone reassembly at the GM-CSF and IL-2 promoters occurs concomitantly with depletion of RelA, c-Rel and RNA polymerase II from the promoters. Furthermore we show that transcriptional down-regulation and chromatin reassembly is dependent on depletion of c-Rel from the nucleus, and that this is regulated by the nuclear t