Comparative Epigenomics of Primate Brains

灵长类动物大脑的比较表观基因组学

• 批准号: 10317211
• 负责人: Genevieve Konopka
• 金额: $ 60万
• 依托单位: UNIVERSITY OF CALIFORNIA SANTA BARBARA
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-17 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10317211
• 关键词: Address; Affect; Anatomy; Area; Brain; Brain region; Candidate Disease Gene; Cellular Structures; Chemicals; Comparative Study; DNA Methylation; DNA analysis; Data; Development; Developmental Process; Disease; Distal; Distant; Enhancers; Epigenetic Process; Event; Evolution; Exhibits; Gene Expression; Gene Expression Profiling; Gene Expression Regulation; Genes; Genetic Risk; Genome; Genomic Segment; Haplorhini; Heterogeneity; Histologic; Human; Immunohistochemistry; Individual; Knowledge; Learning; Link; Macaca mulatta; Mammals; Memory; Methylation; Modification; Molecular; Monkeys; Neuroglia; Neurons; Oligodendroglia; Pan Genus; Pattern; Phenotype; Phylogenetic Analysis; Phylogeny; Play; Pongidae; Pontine structure; Positioning Attribute; Prefrontal Cortex; Primates; Recording of previous events; Research; Resolution; Role; Testing; Tissues; Untranslated RNA; Validation; Variant; Work; brain cell; brain size; cell type; comparative; epigenome; epigenomics; excitatory neuron; inhibitory neuron; insight; methylome; neuropsychiatric disorder; nonhuman primate; novel; promoter; species difference; trait; validation studies

Project Summary Epigenetic modifications are essential chemical modifications that play critical roles in gene regulation, development, and diseases. Therefore, understanding how epigenetic changes between species occur and how they affect gene regulation has potential to advance our knowledge of regulatory evolution. However, the details of epigenetic evolution are sparse, and how epigenetic evolution correlates with phenotype evolution is even less understood. The proposed research will address this gap of knowledge by integrating novel data on DNA methylation with primate brain evolution. Studies of human brains have demonstrated that distinctive brain cell types have substantially different DNA methylation and gene expression, and analyses without separating these cell types can yield misleading results. Additionally, comparative studies of primates and other mammals have shown that the anatomical and cellular structure of brain regions evolve at varying rates as a result of differences in neurodevelopmental events linked to overall brain size. DNA methylation is a key molecular mechanism to record and affect development, and shows difference between brain regions. Therefore, the proposed research will test a novel hypothesis that DNA methylation of distinctive cell types in human and non-human primate brains shows variation consistent with brain size evolution. Moreover, validation studies will be performed for specific candidate genes and genomic regions that show DNA methylation and gene expression difference related to brain region differences and species differences. Specifically, evolutionary histories will be constructed for DNA methylation (Specific Aim 1) and gene expression (Specific Aim 2) from two major subclasses of neurons (excitatory and inhibitory neurons) as well as oligodendrocytes (a major non-neuronal cell) of brains from diverse anthropoid primates, including humans, apes, and monkeys. Highly divergent brain regions in terms of function and anatomy (e.g., prefrontal cortex and the pons) will be compared to connect changes at the phenotypic level to molecular changes. Some of these candidate genes will be further investigated in deeper histological resolution (Specific Aim 3). This study will generate novel data to expand our understanding of epigenetic evolution of brains, and to infer functionally important positions of noncoding genomic regions. Furthermore, it will also provide knowledge on how epigenome changes during evolution and how epigenome evolution correlates with phenotype, which is a fundamental yet currently little understood topic.

项目摘要 表观遗传修饰是必不可少的化学修饰，在基因调节中起关键作用， 发展和疾病。因此，了解物种之间的表观遗传变化是如何发生的 它们如何影响基因调节有可能提高我们对调节进化的了解。但是， 表观遗传进化的细节稀疏，表观遗传进化与表型的演变如何相关 甚至不太了解。拟议的研究将通过整合有关的新数据来解决这一知识的差距 DNA甲基化随着灵长类动物脑的进化。人类大脑的研究表明，独特的 脑细胞类型具有实质不同的DNA甲基化和基因表达，并且没有分析 分离这些细胞类型会产生误导性结果。此外，对灵长类动物和 其他哺乳动物表明，大脑区域的解剖学和细胞结构以不同的速率演变 由于神经发育事件与整体大脑大小相关的差异。 DNA甲基化是钥匙 记录和影响发育的分子机制，并显示大脑区域之间的差异。 因此，拟议的研究将检验一个新的假设，即独特细胞类型的DNA甲基化 人类和非人类灵长类动物的大脑显示出与脑大小的演变一致的变化。而且， 将针对显示DNA的特定候选基因和基因组区域进行验证研究 甲基化和基因表达差异与大脑区域差异和物种差异有关。 具体而言，将构建用于DNA甲基化的进化史（特定目标1）和基因 来自两个主要亚类（兴奋性和抑制神经元）的表达（特定目标2） 作为来自各种人类动物灵长类动物的大脑的少突胶质细胞（一个主要的非神经元细胞），包括人类， 猿猴。在功能和解剖学方面高度不同的大脑区域（例如，前额叶皮层 将比较PON），以将表型水平的变化与分子变化联系起来。其中一些 这些候选基因将在更深入的组织学分辨率中进一步研究（特定目的3）。这项研究 将生成新的数据，以扩展我们对大脑表观遗传进化的理解，并通过功能推断 非编码基因组区域的重要位置。此外，它还将提供有关如何 表观基因组在进化过程中的变化以及表观基因组进化如何与表型相关，这是一个 基本但目前鲜为人知的话题。