Epigenetic Regulation of Hippocampal Synaptic Plasticity

描述（由申请人提供）：长期记忆的巩固和长期突触增强的形成都需要基因转录和从头合成蛋白质。多个系统调节这些转录事件，为学习过程提供了几个控制点。我们的实验室和其他人最近的工作已经证明了表观遗传机制在学习和可塑性中起着至关重要的作用，这项工作揭示了表观遗传控制的破坏和认知障碍之间的联系。抑制组蛋白去乙酰化酶（HDAC）酶可增强小鼠正常记忆并挽救疾病模型中的记忆损伤。尽管这种对转录的表观遗传调控的操纵显示出作为治疗工具的希望，但其功能的潜在机制尚不清楚。Sin3a是一种协同抑制蛋白，通过组蛋白低乙酰化将HDAC酶招募到基因启动子中以维持其抑制。核受体亚家族4 （Nr4a）转录因子，通过环AMP反应元件结合蛋白（CREB）和共激活物CREB结合蛋白（CBP）的组蛋白乙酰化调节，也是Sin3a/HDAC复合物负调控的强有力候选者。Nr4a家族的直接早期基因在神经元激活后立即转录，并且已知Nr4a蛋白调节许多对记忆和可塑性重要的基因的转录。我在此建议并行研究Sin3a和Nr4a转录的作用

DESCRIPTION (provided by applicant): The consolidation of long-term memory and the formation of long-term synaptic potentiation both require gene transcription and de novo protein synthesis. Multiple systems regulate these transcriptional events, offering several points of control over learning processes. Recent work from our lab and others has demonstrated a crucial role for epigenetic mechanisms in learning and plasticity, and this work has revealed links between disruption of epigenetic control and disorders of cognition. Inhibiting histone deacetylase (HDAC) enzymes enhances normal memory and rescue impairments of memory in mouse models of disease. Although this manipulation of the epigenetic regulation of transcription shows promise as a therapeutic tool, the underlying mechanisms of how it functions are unknown. Sin3a is a co-repressor protein that recruits HDAC enzymes to gene promoters to maintain their repression through histone hypoacetylation. The nuclear receptor subfamily 4 (Nr4a) transcription factors, regulated via histone acetylation by the cyclic AMP response element binding protein (CREB) and the co-activator CREB-binding protein (CBP), are also strong candidates for negative regulation by the Sin3a/HDAC complex. The Nr4a family of immediate early genes is transcribed immediately after neuronal activation, and the NR4A proteins are known to regulate the transcription of many genes important for memory and plasticity. I propose here to investigate in parallel the roles of Sin3a and the Nr4a transcription factors in hippocampal synaptic plasticity, and to uncover the identity of their regulatory targets in the hippocampal genome.