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。这一特性对于记忆淋巴细胞至关重要。我们发现转录因子 Oct1 在 T 细胞中平衡白细胞介素 2 (Il2) 方面发挥着重要作用。我们的研究结果表明，Oct1 通过涉及不同染色质修饰复合物的两种相互排斥的机制来调节靶基因转录：通过与 NuRD 关联作为阻遏蛋白，通过与称为 Jmjd1a 的组蛋白去甲基酶关联作为激活蛋白（更准确地说，抗阻遏蛋白）。 Oct1 可以响应 ERK 信号从一种模式切换到另一种模式，即使是同一基因。在静息但先前受到刺激的 T 细胞中，Oct1 使用 Jmjd1a 来防止阴性表观遗传标记的积累和稳定的抑制，从而使 Il2 能够进行与二次刺激相关的更快、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) Oct1 如何在 T 细胞中建立和维持，使用 Il2 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 可以防止多个靶标的稳定抑制，以帮助维持与记忆相关的平衡转录状态。这些实验的成功将消除围绕 Oct1 在这些基因调节中的作用的混乱，并确定记忆 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。我们提出三个目标： 具体目标 1：确定 Oct1 从亲压抑状态切换到亲平衡状态的潜在机制。具体目标 2：确定利用 Oct1 防止抑制的目标基因。具体目标 3：确定 Oct1 抗抑制的功能后果。

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.