Molecular Neuropharmacology and Signaling of Histone H2A.Z

 描述（由申请人提供）：组蛋白亚基交换代表了表观遗传学的一个完整分支，是许多模型系统（包括酵母、植物和癌症）中严格实验的主题，但其在神经系统中的作用几乎未知。我们最近进行了第一次活性诱导组蛋白亚基的体内实验研究 本研究旨在研究神经系统中的组蛋白交换，特别关注啮齿动物海马和皮质中的组蛋白变体H2A.Z。在这些研究中，我们发现，行为经验触发组蛋白亚基交换和随之而来的改变，在成人中枢神经系统的基因转录。脑中经验依赖性组蛋白亚基交换的表征代表了我们对神经系统中活性调节的表观遗传机制的认识向前迈出的重要一步，并为表观遗传学领域提供了对该过程的一般功能的重要见解。这些发现引入了一种新的机制来调节神经元中染色质的三维结构，触发基因读出的伴随改变，并驱动行为中的经验依赖性变化。这些发现也开启了靶向组蛋白亚基交换可能是广泛的CNS疾病（包括药物成瘾、认知障碍和一般的神经可塑性障碍）的治疗干预的新靶点的可能性。鉴于这一背景下的新信息的作用，组蛋白H2A.Z亚基交换在中枢神经系统中，对于这个项目，我们建议追求以下四个具体目标：目标1：为了测试的假设，SIRT 1组蛋白/赖氨酸脱乙酰酶信号级联调节H2A.Z亚基交换神经元。目的2：使用全基因组方法检验H2A.Z控制可塑性相关基因的转录和CpG甲基化的假设。目标3：通过开发足以改变H2 A. Z mRNA和蛋白表达并增强获得长期行为变化的基于反义寡核苷酸的构建体，实现H2 A. Z的选择性药理学抑制。目标4：验证H2A.Z通过控制神经元的突触可塑性和稳态突触缩放来调节神经可塑性的假说。我们 预期我们的研究结果将广泛适用于理解经验和药物诱导的神经可塑性参与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.