Molecular Neuropharmacology and Signaling of Histone H2A.Z

 描述(申请人提供)：组蛋白亚单位交换代表表观遗传学的一个完整分支，在许多模型系统中都是严格实验的对象，包括酵母、植物和癌症，但它在神经系统中的作用几乎是未知的。我们最近首次进行了活性诱导组蛋白亚基的体内实验研究。 神经系统中的交换，特别是在啮齿动物的海马体和皮质中的组蛋白变异体H2A.Z。在这些研究中，我们发现，行为体验触发了组蛋白亚单位交换，并伴随着成年中枢神经系统基因转录的变化。大脑中经验依赖型组蛋白亚单位交换的表征代表着我们在神经系统中活动调节的表观遗传机制方面的知识向前迈出了重要的一步，并为一般的表观遗传学领域提供了对这一过程的一般功能的重要见解。这些发现介绍了一种新的机制，用于调节神经元中染色质的三维结构，引发基因读出的伴随变化，并推动依赖经验的行为变化。这些发现也开启了以组蛋白亚单位交换为靶点的可能性，可能成为治疗广泛中枢神经系统疾病的新靶点，包括药物成瘾、认知障碍和一般神经可塑性障碍。鉴于这一关于组蛋白H_2A.Z亚单位交换在中枢神经系统中作用的新信息的背景，在本项目中，我们建议追求以下四个特定目标：目的1：验证SIRT1组蛋白/赖氨酸去乙酰基酶信号级联调节神经元中H_2A_Z亚单位交换的假设。目的2：用全基因组方法检验H_2A.Z控制可塑性相关基因转录和CpG甲基化的假设。目的：通过构建能够改变H_2A.Z基因和蛋白表达并增强长期行为改变获得的反义寡核苷酸构建物，实现对H_2A.Z的选择性药理抑制。目的：验证H2A.Z通过控制神经元突触可塑性和稳态突触伸缩来调节神经可塑性的假说。我们 预期我们的结果将广泛适用于理解经验和药物诱导的神经可塑性，这些可塑性涉及诱导和维持持久的行为变化。

 DESCRIPTION (provided by applicant): Histone subunit exchange represents an entire branch of epigenetics that is the subject of rigorous experimentation in many model systems, including yeast, plants, and cancer, but its role in the nervous system is virtually unknown. We recently conducted the first in vivo experimental investigation of activity-induced histone subunit exchange in the nervous system, focusing specifically on the histone variant H2A.Z in rodent hippocampus and cortex. In these studies we discovered that behavioral experience triggers histone subunit exchange and attendant alterations in gene transcription in the adult CNS. The characterization of experience- dependent histone subunit exchange in the brain represents a significant step forward in our knowledge of activity-regulated epigenetic mechanisms in the nervous system and provides crucial insights into the general function of this process for the field of epigenetics in general. These findings introduce a novel mechanism for regulating the three-dimensional structure of chromatin in neurons, triggering attendant alterations in gene readout, and driving experience-dependent changes in behavior. These discoveries also open up the possibility that targeting histone subunit exchange may be a novel target for therapeutic intervention in a broad range of CNS disorders, including drug addiction, cognitive disorders, and disorders of neural plasticity in general. Given this background of new information concerning a role for histone H2A.Z subunit exchange in the CNS, for this Project we propose to pursue the following four Specific Aims: Aim 1: To test the hypothesis that the SIRT1 histone/lysine de-acetylase signaling cascade regulates H2A.Z subunit exchange in neurons. Aim 2: To test the hypothesis that H2A.Z controls transcription and CpG methylation of plasticity- associated genes using a genome-wide approach. Aim 3: To enable the selective pharmacologic inhibition of H2A.Z by developing antisense oligonucleotide-based constructs that are sufficient to alter H2A.Z mRNA and protein expression and augment the acquisition of long-term behavioral change. Aim 4: To test the hypotheses that H2A.Z regulates neural plasticity via controlling both synaptic plasticity and homeostatic synaptic scaling in neurons. We anticipate that our results will be broadly applicable to understanding experience- and drug-induced neural plasticity involved in the induction and maintenance of lasting behavioral change.