Comparative Epigenomics of Primate Brains

项目摘要 表观遗传修饰是在基因调控中发挥关键作用的基本化学修饰， 发展和疾病。因此，理解物种之间的表观遗传变化是如何发生的 它们是如何影响基因调控的，有可能促进我们对调控进化的了解。然而， 表观遗传进化的细节很少，表观遗传进化如何与表型进化相关 更不为人所知。拟议的研究将通过整合新的数据来解决这一知识差距 DNA甲基化与灵长类大脑进化。对人类大脑的研究表明，这种独特的 脑细胞类型有很大不同的DNA甲基化和基因表达，分析没有 分离这些细胞类型可能会产生误导性的结果。此外，灵长类和灵长类的比较研究 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 这是由于神经发育事件的差异与整体大脑大小有关。DNA甲基化是一个关键 分子机制记录和影响发育，并表现出不同脑区的差异。 因此，这项拟议的研究将检验一个新的假设，即不同细胞类型的DNA甲基化在 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。此外， 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差异和物种差异有关。 具体来说，将构建DNA甲基化(特定目标1)和基因的进化史 两大类神经元(兴奋性神经元和抑制性神经元)的表达(特异靶2) 作为来自包括人类在内的各种类人灵长类动物大脑的少突胶质细胞(一种主要的非神经细胞)， 类人猿和猴子。在功能和解剖方面高度不同的大脑区域(例如，前额叶皮质 和脑桥)进行比较，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层次的组织学分辨率(特定目标3)中进一步研究。本研究 将产生新的数据，以扩大我们对大脑表观遗传进化的理解，并从功能上推断 非编码区的重要位置。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，这是一种 基本但目前鲜为人知的话题。

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.