Role of Transcription Coactivator OCA-B in Gene Poising and Immunological Memory

转录辅激活因子 OCA-B 在基因平衡和免疫记忆中的作用

• 批准号: 10084248
• 负责人: DEAN TANTIN
• 金额: $ 48.5万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-12-01 至 2022-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10084248
• 关键词: Address; Alleles; Antitumor Response; Autoimmune; Autoimmune Diseases; Autoimmunity; Bypass; CD4 Positive T Lymphocytes; CD8-Positive T-Lymphocytes; Cells; Chromatin; Communicable Diseases; Defect; Development; Distant; Docking; Environment; Foundations; Gene Expression; Genes; Genetic Transcription; Genome; Histones; Hypersensitivity; Immunologic Memory; In Vitro; Infection; Label; Lightning; Link; Lymphocytic choriomeningitis virus; Lysine; MHV-JHM; Maintenance; Mediating; Membrane; Memory; Molecular; Murine hepatitis virus; Mus; Nuclear; OX40; Peptides; Permeability; Pharmacology; Phenotype; Protein Isoforms; Proteins; Publishing; Repression; Rest; Role; Stimulus; T cell response; T-Cell Development; T-Lymphocyte; Testing; Transcription Coactivator; Transcription Factor AP-1; Tumor Immunity; Viral; Virus Diseases; Work; chromatin modification; chronic infection; cytokine; experimental study; immunopathology; immunoregulation; in vivo; inhibitor/antagonist; mutant; nuclear factors of activated T-cells; pathogen; precursor cell; prospective; public health relevance; recruit; response; transcription factor; vaccine development

PROJECT SUMMARY: Immunological memory provides critical protection against pathogens and can drive autoimmune and anti- tumor responses, but our understanding of the underlying molecular mechanisms is inadequate. The transcriptional co-regulator OCA-B (also known as Bob.1, OBF-1 and Pou2af1) is induced in stimulated primary CD4 T cells, where it docks with its cognate transcription factor Oct1 to regulate critical targets – among them Il2, Il21, Ifng, Icos, Ctla4, Csf2 (Gmscf), Tnfrsf4 (Ox40), Tbx21 (Tbet), and Stat5a. OCA-B’s effects do not manifest upon simple stimulation of CD4 T cells. Instead, withdrawing the stimulus, then resting and re-stimulating OCA-B deficient cells results in gene expression defects of 100-fold or more. OCA-B mediates these effects by recruiting the Jmjd1a histone lysine demethylase to remove inhibitory histone H3K9me2 chromatin modifications at silent but previously activated target loci. In vivo, both OCA-B and Oct1 are dispensable for T cell development and primary CD4 response but required for CD4 memory formation and response to re-challenge1. This published foundational work leads to many unanswered questions: Can OCA-B be used to prospectively identify CD4 memory cells? Can it directly drive memory? What is its role in CD8 cells? In autoimmunity? In anti-tumor immunity? Why are OCA-B target genes frequently adjacent to one another as linked gene pairs? Can OCA-B be targeted pharmacologically? Our proposal addresses these questions. The overarching hypothesis is that in both CD4 and CD8 T cells, OCA-B coordinately regulates the expression of genes encoding cytokines and other immunomodulatory proteins to control pathogen response and memory cell formation. Aim 1: Determine if Jmjd1a recruitment by myristoylated OCA-B promotes CD4 memory. Aim 2: Determine the role of OCA-B in chronic infection. Aim 3: Determine if myristoylated OCA-B facilitates interactions between distant loci.

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