Role of Oct Transcription Factors Regulating Immune Response

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。这种特性对记忆淋巴细胞至关重要。我们发现，转录因子Oct1在平衡T细胞中的白细胞介素2（IL 2）中起着重要作用。我们的研究结果表明，Oct1通过两种相互排斥的机制调节靶基因的转录，涉及不同的染色质修饰复合物：通过与NuRD相关作为阻遏物，以及通过与称为Jmjd1a的组蛋白去甲基化酶相关作为激活物（更准确地说，抗阻遏物）。Oct1可以从一种模式切换到另一种模式，即使在同一个基因上，响应ERK信号。在静息但先前受刺激的T细胞中，Oct1使用Jmjd1a来防止负表观遗传标记的积累和稳定的抑制，从而使IL 2与次级刺激相关的更快速和更强的诱导。Oct1对于维持CD4记忆T细胞的数量和功能也至关重要。该提案将确定1）如何在T细胞中建立和维持Oct1转换为抗阻遏，使用IL 2作为模型靶标，2）Oct1是否以相同的方式调节多个靶基因，以及3）生理后果。我们的中心假设是，Oct1阻止了多个靶点的稳定抑制，以帮助维持与记忆相关的稳定转录状态。这些实验的成功将消除围绕Oct1在这些基因调控中的作用的混乱，并确定记忆T细胞将关键基因保持在稳定的表观遗传状态以供以后表达的机制。我们提出了三个目标：具体目标1：确定Oct1从亲压抑状态转换到亲平衡状态的机制。具体目标2：确定利用Oct1防止阻遏的靶基因。具体目标3：确定Oct1抗阻遏的功能后果。

DESCRIPTION (provided by applicant): Cells must maintain some genes in a silent state while keeping them poised for later expression. This property is critical for memory lymphocytes. We found that a transcription factor, Oct1, plays a major role in poising interleukin-2 (Il2) in T cells. Our findings indicate that Oct1 regulates target gene transcription through two mutually exclusive mechanisms involving different chromatin modifying complexes: as a repressor through association with NuRD, and as an activator (more accurately, anti-repressor) through association with a histone demethylase known as Jmjd1a. Oct1 can switch from one mode to the other, even at the same gene, in response to ERK signaling. In resting but previously stimulated T cells, Oct1 uses Jmjd1a to prevent the accumulation of negative epigenetic marks and stable repression, thus poising Il2 for the more rapid and stronger induction associated with secondary stimulation. Oct1 is also critical for maintaining CD4 memory T cell numbers and function. This proposal will determine 1) how Oct1 switching to anti-repression is established and maintained in T cells, using Il2 as a model target, 2) whether Oct1 regulates multiple target genes in the same manner, and 3) the physiological consequences. Our central hypothesis is that Oct1 prevents stable repression of multiple targets, to help maintain a poised transcriptional state associated with memory. Success with these experiments will eliminate the confusion surrounding the role of Oct1 in the regulation of these genes, and identify a mechanism by which memory T cells maintain critical genes in poised epigenetic states for later expression. We propose three aims: Specific Aim 1: Determine the mechanism underlying Oct1 switching from a pro- repressive to a pro-poising state. Specific Aim 2: Identify the target genes that utilize Oct1 to prevent repression. Specific Aim 3: Determine the functional consequences of Oct1 anti-repression.