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。我们先前的发现表明，Oct1转录因子对于稳定IL2基因是关键的，因为与二次T细胞刺激相关的更快和更强的诱导。Oct1对于维持CD4 Memory T细胞的数量和功能也是至关重要的(未公布的数据)。然而，我们的发现不能解释为什么Oct1靶基因在T细胞激活后的很长时间内在记忆细胞中保持转录稳定。我们的中心假设是，OCA-B，一种已知与Oct1对接的转录辅助激活因子，阻止了多个靶点的稳定抑制，以帮助维持与免疫记忆相关的稳定转录状态。这一建议将决定1)OCA-B在IL2基因座上基因平衡的机制，2)OCA-B准备稍后表达的靶基因的数量和识别，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细胞将关键基因保持在稳定的表观遗传状态以便以后表达的机制，并揭示免疫记忆的中央调节因素。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。具体目标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。

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 Oct1 is also critical for maintaining CD4 memory T cell numbers and function (unpublished data).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