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: 8585815
• 负责人: DEAN TANTIN
• 金额: $ 37.25万
• 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 2017-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8585815
• 关键词: CD4 Positive T Lymphocytes; Cell Count; Cell physiology; Cells; Data; Defect; Dissection; Docking; Epigenetic Process; Gene Expression; Gene Targeting; Generations; Genes; Immunologic Memory; Indium; Infection; Lymphocyte; Maintenance; Mediating; Memory; Modeling; Property; Regulation; Repression; Role; T memory cell; T-Cell Activation; T-Lymphocyte; Testing; Transcription Coactivator; in vivo; memory CD4 T lymphocyte; mouse model; pathogen; prevent; programs; public health relevance; research study; response; success; transcription factor

DESCRIPTION (provided by applicant): Cells must maintain some genes in a silent state while simultaneously keeping them poised for later expression. This property is critical for memory lymphocytes, however the mechanisms are unclear. Our prior findings showed that the Oct1 transcription factor is critical for poising the Il2 gene for the more rapid and stronger induction associated with secondary T cell stimulation. Oct1 is also critical for maintaining CD4 memory T cell numbers and function (unpublished data). However, our findings do not explain how Oct1 target genes remain transcriptionally poised in memory cells at long timepoints following T cell activation. Our central hypothesis is that OCA-B, a transcriptional co-activator known to dock with Oct1, prevents stable repression of multiple targets, to help maintain poised transcriptional states associated with immunological memory. This proposal will determine 1) the mechanism of gene poising by OCA-B at the Il2 gene locus, 2) the number and identity of target genes poised for later expression by OCA-B and 3) the capacity of OCA-B to regulate memory T cell states in vivo. Success with these experiments will identify the mechanism whereby CD4 memory T cells maintain critical genes in poised epigenetic states for later expression, and uncover a central regulator of immunological memory. Specific Aim 1: Determine the mechanism by which OCA-B maintains Il2 in a poised transcriptional state as part of the epigenetic program that maintains memory functionality. Specific Aim 2: Identify the target genes that utilize OCA-B to prevent stable repression. Specific Aim 3: Determine the in vivo consequences of OCA-B anti-repression.

描述（由申请人提供）：细胞必须保持一些基因处于沉默状态，同时保持它们为以后的表达做好准备。这种特性对于记忆淋巴细胞至关重要，但其机制尚不清楚。我们之前的研究结果表明，Oct1 转录因子对于平衡 Il2 基因以实现与二次 T 细胞刺激相关的更快、更强的诱导至关重要。 Oct1 对于维持 CD4 记忆 T 细胞数量和功能也至关重要（未发表的数据）。然而，我们的研究结果并没有解释 Oct1 靶基因如何在 T 细胞激活后的很长一段时间内在记忆细胞中保持转录平衡。我们的中心假设是 OCA-B（一种已知与 Oct1 对接的转录共激活因子）可防止多个靶标的稳定抑制，以帮助维持与免疫记忆相关的平衡转录状态。该提案将确定 1) OCA-B 在 Il2 基因座上的基因平衡机制，2) OCA-B 稍后表达的靶基因的数量和身份，以及 3) OCA-B 调节体内记忆 T 细胞状态的能力。这些实验的成功将确定 CD4 记忆 T 细胞将关键基因维持在表观遗传状态以供以后表达的机制，并揭示免疫记忆的中央调节因子。具体目标 1：确定 OCA-B 将 Il2 维持在平衡转录状态的机制，作为维持记忆功能的表观遗传程序的一部分。具体目标 2：确定利用 OCA-B 防止稳定抑制的靶基因。具体目标 3：确定 OCA-B 抗抑制作用的体内后果。