The Role of Histone Variant H3.3 and miR-128 in Learned Vocal Communication

组蛋白变体 H3.3 和 miR-128 在学习性语音交流中的作用

• 批准号: 9262050
• 负责人: Caitlin Marie Aamodt
• 金额: $ 3.52万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 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 2020-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9262050
• 关键词: Acetylation; Adult; Affect; Age; Animal Model; Area; Basal Ganglia; Behavior; Behavioral; Behavioral Mechanisms; Birds; Brain region; Cell Nucleus; ChIP-seq; Chromatin; Cognition; Cognition Disorders; Communication; Complex; Control Animal; Corpus striatum structure; Data; Data Set; Development; Drug Targeting; Early Intervention; Epigenetic Process; Exposure to; Family; Gene Expression; Genes; Histone Acetylation; Histone Deacetylase Inhibitor; Histone H3; Histone H3.3; Histones; Human; Intellectual functioning disability; Investigation; Language; Lead; Learning; Life; Link; Mediating; Methylation; MicroRNAs; Modeling; Modification; Molecular; Mus; Neuraxis; Parents; Pathology; Pathway Analysis; Patients; Pharmaceutical Preparations; Post-Translational Protein Processing; Process; Puberty; Regulation; Reporting; Repression; Research; Role; Shapes; Small Interfering RNA; Social Environment; Social isolation; Songbirds; Speech; Speech Therapy; Study models; Testing; Thalamic structure; Therapeutic; Tissue Sample; Transcriptional Activation; Up-Regulation; Variant; Weight; Work; autism spectrum disorder; base; chromatin remodeling; critical developmental period; critical period; data mining; design; developmental disease; environmental intervention; epigenetic regulation; experience; ginsenoside Rh2; hatching; histone methylation; histone modification; improved; knock-down; novel; phonology; prevent; research study; social; stereotypy; syntax; therapeutic target; transcriptome sequencing; tutoring; vocal learning; vocalization; zebra finch

Project Summary The molecular study of cognition has been revolutionized by the discovery of experience-dependent epigenetic remodeling. The mechanisms underlying these processes have been implicated in autism spectrum disorders and other forms of intellectual disability that are associated with communication deficits. Epigenetic mechanisms are promising therapeutic targets for developmental disorders because they could potentially enhance the efficacy of environmental interventions such as speech therapy. Songbirds are the commonly used model for human speech, as they allow for behavioral experiments designed to understand the molecular basis of learned vocal communication. Unlike other model organisms, zebra finches learn complex vocalizations from observing adults in the social environment. Work from our lab and others reveals that dynamic behavioral regulation of song- and language-related genes such as FoxP2 underlies learned vocal communication, but the mechanistic basis for this awaits further characterization. We previously used Weighted Gene Co-Expression Network Analysis to show that in the striatal song nucleus Area X, changes in the expression of histone H3 methylation erasers, microRNA-128, and the transcriptional regulator histone variant H3.3 are significantly correlated with singing. In contrast, these changes are not observed in a neighboring striatal region that does not control song. From this data set I developed a working model whereby singing induces activity-dependent miR-128 expression, which then alters repressive transcriptional machinery levels in order to expose certain song-regulated genes for H3.3 exchange and transcriptional activation. To test this hypothesis, I raised zebra finches in isolation such that they developed an impoverished song. I then reintroduced them as adults to a tutor and administered daily treatments of the miR-128 activator ginsenoside Rh2 (GRh2) or vehicle as a control. Excitingly, GRh2 significantly ameliorated deficits in syntax stereotypy, allowing the bird to organize his song and reproduce it with high fidelity. I will investigate how GRh2 rescues communication deficits by first characterizing the social isolate model using RNA sequencing and chromatin immunoprecipitation sequencing. I will then generate a siRNA construct to knock down miR-128 in Area X and analyze how this affects song and gene expression using RNAseq. I will then rescue social isolation-induced communication deficits with GRh2 and compare the results to an HDAC inhibitor, a class of drugs that has shown promise in animal models of intellectual disability as well as human patients. This study will break new ground by testing the links between dynamic chromatin changes and learned vocal communication and introduce GRh2 as a novel epigenetic therapeutic for cognitive disorders.

项目摘要 认知的分子研究因经验依赖性表观遗传的发现而发生了革命性的变化 重塑这些过程背后的机制与自闭症谱系障碍有关 以及其他形式的与沟通缺陷相关的智力残疾。后生 机制是有前途的治疗目标，为发展障碍，因为他们可能 提高环境干预的效果，如语言治疗。鸣禽通常是 使用人类语言的模型，因为它们允许行为实验，旨在了解分子 学习声乐交流的基础。与其他模式生物不同，斑胸草雀学习复杂的 观察成年人在社会环境中的发声。我们实验室和其他人的工作表明， 歌曲和语言相关基因（如FoxP 2）的动态行为调节是学习声乐的基础 通信，但这有待进一步表征的机械基础。我们以前使用 加权基因共表达网络分析表明，在纹状体鸣唱核X区， 组蛋白H3甲基化擦除器、microRNA-128和转录调节因子组蛋白的表达 变异H3.3与歌唱显著相关。相比之下，这些变化在 邻近的纹状体区域，不控制歌曲。从这个数据集，我开发了一个工作模型， 唱歌诱导活性依赖性miR-128表达，然后改变抑制性转录机制 水平，以暴露某些歌曲调节基因的H3.3交换和转录激活。测试 根据这个假设，我把斑胸草雀隔离起来，这样它们就发展出了一种贫乏的歌声。然后我 成年后，他们被重新介绍给导师，并每天给予miR-128激活剂治疗。 Rh 2（GRh 2）或溶剂作为对照。令人兴奋的是，GRh 2显著改善了句法刻板性的缺陷， 让鸟儿组织自己的歌声并以高保真度再现。我将研究GRh 2如何拯救 通过首先使用RNA测序和染色质表征社会隔离模型， 免疫沉淀测序。然后，我将产生一个siRNA构建体来敲低X区域中的miR-128， 使用RNAseq分析这如何影响歌曲和基因表达。然后我会拯救社会孤立导致的 与GRh 2的沟通缺陷，并将结果与HDAC抑制剂进行比较，HDAC抑制剂是一类具有 在智力残疾的动物模型和人类患者中显示出希望。这项研究将打破新的 通过测试动态染色质变化和习得的声音交流之间的联系， 引入GRh 2作为认知障碍新型表观遗传治疗剂。