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: 8457551
• 负责人: DEAN TANTIN
• 金额: $ 35.08万
• 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/8457551
• 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 Oct1 is also critical for maintaining CD4 memory T cell numbers and function (unpublished data).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）：细胞必须将某些基因保持在静默状态，同时使它们保持平衡以进行以后的表达。该特性对于记忆淋巴细胞至关重要，但是机制尚不清楚。我们先前的发现表明，OCT1转录因子对于在与继发性T细胞刺激相关的更快和更强的诱导方面对IL2基因的固定至关重要。 OCT1对于维持CD4存储器T细胞数量和功能（未发表的数据）也至关重要。但是，我们的发现并未解释OCT1靶基因在T细胞激活后长时间的长时间记忆细胞中如何保持转录固定。我们的中心假设是，OCA-B是已知与OCT1对接的转录共激活器，可防止对多个目标的稳定抑制，以帮助维持与免疫学记忆相关的固定转录状态。该建议将确定1）OCA-B在IL2基因基因座上抗性的基因机制，2）靶基因的数量和身份，可通过OCA-B和3）OCA-B的能力在体内调节记忆T细胞状态的能力。这些实验的成功将确定CD4记忆T细胞在有固定的表观遗传态中保持关键基因的机制，以供以后表达，并发现免疫记忆的中心调节剂。具体目标1：确定OCA-B在保持记忆功能的表观遗传程序的一部分中，OCA-B将IL2保持在固定的转录状态的机制。特定目标2：确定利用OCA-B来防止稳定抑制的靶基因。具体目标3：确定OCA-B抗抑制的体内后果。