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

项目概要： 免疫记忆提供了对病原体的关键保护，并可以驱动自身免疫和抗- 肿瘤反应，但我们对潜在的分子机制的理解是不够的。的 转录辅助调节因子OCA-B（也称为Bob.1、OBF-1和Pou 2af 1）在受刺激的细胞中被诱导， 初级CD 4 T细胞，在那里它与其同源转录因子Oct 1对接以调节关键靶点- 其中包括Il 2、Il 21、Ifng、Icos、Ctla 4、Csf 2（Gmscf）、Tnfrsf 4（Ox 40）、Tbx 21（Tbet）和Stat 5a。OCA-B's 对CD 4 T细胞的简单刺激不显示效果。相反，取消刺激计划， 静止和再刺激OCA-B缺陷细胞导致100倍或更多的基因表达缺陷。 OCA-B通过募集Jmjd 1a组蛋白赖氨酸去甲基化酶来消除抑制因子， 组蛋白H3 K9 me 2染色质修饰沉默，但先前激活的靶基因座。在体内，OCA-B 和Oct 1是T细胞发育和初级CD 4应答的关键，但对于CD 4记忆是必需的 形成和响应再挑战1.这一出版的基础性工作导致许多未回答的问题， 问题：OCA-B能否用于前瞻性识别CD 4记忆细胞？它能直接驱动内存吗？ 它在CD 8细胞中的作用是什么？在自身免疫性疾病？在抗肿瘤免疫方面？为什么OCA-B靶基因 作为连锁基因对经常彼此相邻吗？OCA-B可以成为目标吗？我们 提案针对这些问题。总体假设是，在CD 4和CD 8 T细胞中， OCA-B协调调节编码细胞因子和其他免疫调节因子的基因的表达。 控制病原体反应和记忆细胞形成的蛋白质。目标1：确定Jmjd 1a是否招募 肉豆蔻酰化OCA-B促进CD 4记忆。目的2：确定OCA-B在慢性感染中的作用。 目的3：确定豆蔻酰化OCA-B是否促进了远距离基因座之间的相互作用。

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.