Depletion of c-Rel from cytokine gene promoters is required for chromatin reassembly and termination of gene responses to T cell activation

• Published in: PloS one Vol. 7; no. 7; p. e41734
• Main Authors: Poke, Fiona S, Upcher, William R, Sprod, Owen R, Young, Arabella, Brettingham-Moore, Kate H, Holloway, Adele F
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 30.07.2012; Public Library of Science (PLoS)
• Subjects: Activation; Animals; Binding sites; Biology; Cell activation; Cell Line; Cell Nucleus - metabolism; Chromatin; Chromatin Assembly and Disassembly; Chromatin remodeling; Colony-stimulating factor; Depletion; DNA binding proteins; DNA-directed RNA polymerase; Down-Regulation; Gene expression; Gene regulation; Genes; Genetic aspects; Granulocyte-macrophage colony-stimulating factor; Granulocyte-Macrophage Colony-Stimulating Factor - genetics; Granulocyte-Macrophage Colony-Stimulating Factor - metabolism; Histones; Histones - metabolism; I-kappa B Proteins - metabolism; Immune response; Immune system; Inflammation; Interleukin; Interleukin 2; Interleukin-2 - genetics; Interleukin-2 - metabolism; Interleukins; Kinases; Leukocytes (granulocytic); Lymphocyte Activation; Lymphocytes T; Macrophage colony stimulating factor; Macrophages; Medicine; Mice; NF-KappaB Inhibitor alpha; NF-κB protein; Nuclear transport; Promoter Regions, Genetic; Promoters; Protein Binding; Protein Transport; Proteolysis; Proto-Oncogene Proteins c-rel - metabolism; Proto-Oncogene Proteins c-rel - physiology; RelA protein; Remodeling; Ribonucleic acid; RNA; RNA polymerase II; RNA Polymerase II - metabolism; RNA, Messenger - genetics; RNA, Messenger - metabolism; Rodents; T cell receptors; T cells; T-Lymphocytes - immunology; T-Lymphocytes - metabolism; Transcription (Genetics); Transcription activation; Transcription, Genetic; Translocation; Australia; Tasmania Australia
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0041734

The role of the Nuclear Factor κB (NF-κB) 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 translocation of the NF-κB inhibitor, IκBα. The nuclear activation of c-Rel therefore not only regulates the initiation of GM-CSF and IL-2 gene activation in response to T cell activation, but also the termination of these gene responses following the removal of the activating signal.