Molecular Neuropharmacology and Signaling of Histone H2A.Z

组蛋白 H2A.Z 的分子神经药理学和信号转导

• 批准号: 9480880
• 负责人: ROGER J COLBRAN
• 金额: $ 39.25万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-02-01 至 2022-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9480880
• 关键词: Acetylesterase; Address; Adult; Aging; Antisense Oligonucleotides; Area; Automobile Driving; Behavior; Behavioral; Binding; Biological Models; Brain; Cell Differentiation process; Cells; Central Nervous System Diseases; Chromatin; Chromatin Structure; Cognition; Cognition Disorders; Complex; Cytosine; DNA; DNA Methylation; DNA Structure; Development; Developmental Biology; Disease; Drug Addiction; Epigenetic Process; Gene Activation; Gene Expression; Gene Expression Regulation; Gene Mutation; Gene Targeting; Genes; Genetic Transcription; Hippocampus (Brain); Histone H2A; Histones; Interphase Cell; Investigation; Knowledge; Lysine; Maintenance; Malignant Neoplasms; Mediating; Memory; Mental disorders; Methylation; Mitotic; Modification; Molecular; Nervous system structure; Neuronal Plasticity; Neurons; Neuropharmacology; Nucleosomes; Pharmaceutical Preparations; Pharmacology; Plants; Post-Translational Protein Processing; Process; Property; Protein Isoforms; Regulation; Rodent; Role; SIRT1 gene; Signal Pathway; Signal Transduction; Stimulus; Synapses; Synaptic plasticity; Testing; Therapeutic Intervention; Transcriptional Regulation; Variant; Yeasts; base; behavior change; cognitive enhancement; conditioned fear; experience; fascinate; gene repression; genome-wide; histone modification; in vivo; insight; knock-down; long term memory; mRNA Expression; memory consolidation; neural circuit; neuromechanism; neuroregulation; new therapeutic target; novel; particle; preclinical study; protein expression; public health relevance; therapeutic development; three dimensional structure; virtual

 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.

 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，它是许多模型系统（包括酵母、植物和癌症）中严格实验的主题，但它在神经系统中的作用实际上是未知的。我们最近对活性诱导的组蛋白亚基进行了首次体内实验研究 神经系统中的交换，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，我们发现行为体验会触发成体中枢神经系统中组蛋白亚基交换和随之而来的基因转录改变。大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动调节的表观遗传机制的认识向前迈出了重要一步，并为表观遗传学领域的这一过程的一般功能提供了重要的见解。这些发现引入了一种新的机制，用于调节神经元染色质的三维结构，引发基因读数的随之变化，并驱动依赖于经验的行为变化。这些发现还开辟了一种可能性，即靶向组蛋白亚基交换可能是治疗干预广泛的中枢神经系统疾病的新靶标，包括药物成瘾、认知障碍和一般神经可塑性障碍。鉴于有关组蛋白 H2A.Z 亚基交换在 CNS 中的作用的新信息背景，我们建议在本项目中追求以下四个具体目标： 目标 1：检验 SIRT1 组蛋白/赖氨酸脱乙酰酶信号级联调节神经元中 H2A.Z 亚基交换的假设。目标 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：通过开发基于反义寡核苷酸的构建体来实现对 H2A.Z 的选择性药理学抑制，该构建体足以改变 H2A.Z mRNA 和蛋白质表达并增强长期行为改变的获得。目标 4：测试 H2A.Z 通过控制神经元突触可塑性和稳态突触缩放来调节神经可塑性的假设。我们 预计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行为改变。