Comparative Epigenomics of Primate Brains

灵长类动物大脑的比较表观基因组学

基本信息

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
项目类别：
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

项目摘要

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.

项目概要表观遗传修饰是重要的化学修饰，在基因调控中发挥关键作用，发育、疾病等。因此，了解物种之间的表观遗传变化如何发生并它们如何影响基因调控有可能增进我们对调控进化的了解。然而，表观遗传进化的细节很少，而表观遗传进化与表型进化的关系如何更不明白了。拟议的研究将通过整合新数据来解决这一知识差距 DNA 甲基化与灵长类动物大脑进化。对人类大脑的研究表明，独特的脑细胞类型具有显着不同的 DNA 甲基化和基因表达，并且无需进行分析分离这些细胞类型可能会产生误导性的结果。此外，灵长类动物和其他哺乳动物已经表明，大脑区域的解剖和细胞结构以不同的速度进化这是与大脑整体大小相关的神经发育事件差异的结果。 DNA甲基化是关键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，即不同细胞类型的 DNA 甲基化人类和非人类灵长类动物的大脑表现出与大脑大小进化一致的变化。而且，将对显示 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脑区域差异和物种差异有关。具体来说，将为 DNA 甲基化（具体目标 1）和基因构建进化历史。两个主要神经元亚类（兴奋性神经元和抑制性神经元）的表达（具体目标 2）作为包括人类在内的多种类人灵长类动物大脑的少突胶质细胞（一种主要的非神经元细胞），猿猴。在功能和解剖结构方面高度分化的大脑区域（例如，前额皮质和脑桥）将进行比较，以将表型水平的变化与分子变化联系起来。一些这些候选基因将以更深入的组织学分辨率进行进一步研究（具体目标 3）。这项研究将产生新的数据来扩展我们对大脑表观遗传进化的理解，并推断功能非编码基因组区域的重要位置。此外，它还将提供有关如何进化过程中表观基因组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很少被理解的主题。