Role of transcription coactivator OCA-B in gene poising and immunological memory.

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Il2基因的定位至关重要，与继发性T细胞刺激相关的诱导更快、更强。Oct1对于维持CD4记忆T细胞的数量和功能也至关重要（未发表的数据）。然而，我们的发现并不能解释Oct1靶基因如何在T细胞激活后的长时间点上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，可以阻止多个靶标的稳定抑制，从而帮助维持与免疫记忆相关的转录状态。本研究将确定1)OCA-B在Il2基因位点的基因定位机制，2)OCA-B准备随后表达的靶基因的数量和身份，以及3)OCA-B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细胞将关键基因维持在稳定的表观遗传状态以供后期表达的机制，并揭示免疫记忆的中心调节因子。具体目标1：确定OCA-B维持Il2处于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。特异性目标2：确定利用OCA-B阻止稳定抑制的靶基因。特异性目的3：确定OCA-B抗抑制的体内结果。

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 Oct1 is also critical for maintaining CD4 memory T cell numbers and function (unpublished data).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.