Comparative Epigenomics of Primate Brains

项目摘要 表观遗传修饰是在基因调控中起关键作用的基本化学修饰， 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控有可能促进我们对调控进化的认识。但 表观遗传进化的细节是稀疏的，表观遗传进化与表型进化的关系是 更不被理解。拟议的研究将通过整合以下方面的新数据来解决这一知识缺口： DNA甲基化与灵长类大脑进化对人类大脑的研究表明， 脑细胞类型具有实质上不同的DNA甲基化和基因表达，并且分析没有 分离这些细胞类型会产生误导性的结果。此外，对灵长类动物和 其他哺乳动物的大脑区域的解剖学和细胞结构以不同的速度进化 这是由于与大脑整体大小相关的神经发育事件的差异。DNA甲基化是关键 分子机制来记录和影响发育，并显示大脑区域之间的差异。 因此，拟议的研究将测试一个新的假设，即不同细胞类型的DNA甲基化， 人类和非人类灵长类动物大脑显示出与大脑大小进化一致的变化。此外，委员会认为， 验证研究将针对特定的候选基因和显示DNA 甲基化和基因表达差异与脑区差异和种属差异有关。 具体而言，将构建DNA甲基化（特定目标1）和基因的进化历史。 表达（特异性目标2）的两个主要亚类的神经元（兴奋性和抑制性神经元），以及 作为来自包括人类在内的多种灵长类动物的脑的少突胶质细胞（一种主要的非神经元细胞）， 猿和猴子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 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。一些 这些候选基因将在更深的组织学分辨率中被进一步研究（Specific Aim 3）。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， 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与表型的关系，这是一个 这是一个基本的，但目前还不太了解的话题。

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.