Discovering human divergent activity-regulated elements using comparative, computational, and functional approaches

使用比较、计算和功能方法发现人类不同活动调节的元素

• 批准号: 10779701
• 负责人: KATHERINE S. POLLARD
• 金额: $ 83.21万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-15 至 2028-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10779701
• 关键词: Address; Atlases; Autopsy; Behavioral; Biological Assay; Biological Models; Brain; CRISPR interference; Chromatin; Cognitive; Computer Models; Computing Methodologies; Data; Data Set; Development; Diploidy; Disease; Elements; Enhancers; Evolution; Gene Expression; Gene Expression Regulation; Genes; Genetic; Genetic Variation; Genetic study; Genome; Genomics; Human; In Vitro; Induced pluripotent stem cell derived neurons; Life Experience; Link; Location; Macaca; Macaca mulatta; Machine Learning; Mediator; Methods; Modeling; Molecular; Mutation; Neurodevelopmental Disorder; Neuronal Plasticity; Neurons; Pan Genus; Pattern; Phase; Phenotype; Phylogeny; Physiological; Prevalence; Primates; Property; Regulator Genes; Regulatory Element; Reporter; Resources; Sequence Analysis; Slice; Statistical Data Interpretation; Stimulus; Training; Variant; cognitive ability; comparative; convolutional neural network; developmental plasticity; experience; flexibility; genome-wide; innovation; machine learning model; nervous system disorder; nonhuman primate; response; sequence learning; single-cell RNA sequencing; species difference; stem cells

PROJECT SUMMARY New experiences elicit distinct patterns of brain activity, leading to the changes in gene expression, neuronal properties, and connectivity that underlie brain plasticity. In humans, the period of enhanced plasticity during brain development is particularly protracted compared to other species. However, the mechanisms and extent to which human neurons have changed to support increased plasticity remain unknown. Furthermore, although prolonged developmental plasticity may support increased cognitive capabilities and behavioral flexibility, it may also increase vulnerability to neurodevelopmental disorders. Neuronal plasticity depends on activity-regulated changes in gene expression that are controlled by activity-responsive genomic regulatory elements. Although we and others have identified regulatory elements as prominent substrates of human-specific evolutionary change, recent atlases of postmortem human and non-human primate brains overlook such dynamic stimulus- responsive regulatory elements. Without training on context-dependent data, current computational models that infer regulatory function based on sequence fail to predict activity-dependent regulatory elements. We hypothesize that there have been genetic changes in human divergent activity-regulated elements (hDAREs) and that we can discover these human-specific genetic underpinnings of plasticity using genome-wide approaches. We will use experimental and computational methods to predict and compare the activity-regulated responses of human neurons versus neurons from rhesus macaque and chimpanzee. We have developed innovative model systems that will allow us to stimulate physiological activity states in previously inaccessible primate neurons, machine learning models to predict regulatory function based on sequence, and massively parallel reporter assays and CRISPRi assays that will allow us to assess the function of candidate hDAREs. Through the successful completion of these studies, we will determine which genomic elements and genetic changes underlie activity-dependent responses in human neurons and the extent to which changes in these elements represent a major substrate of evolutionary selection in the human lineage. This will lay the groundwork for further phenotypic characterization of cellular plasticity mechanisms in the developing human brain. Additionally, these datasets will provide a valuable resource for dissecting genetic mechanisms of neurodevelopmental disorders.

项目摘要 新体验引起了大脑活动的不同模式，导致基因表达的变化，神经元 大脑可塑性构成的特性和连通性。在人类中，在人类中增强了可塑性的时期 与其他物种相比，大脑发育特别持久。但是，机制和程度 人类神经元已更改以支持增加的可塑性仍然未知。此外，虽然 长时间的发育可塑性可能支持提高认知能力和行为灵活性，它可能 还增加了神经发育障碍的脆弱性。神经元可塑性取决于活动调节 受活性响应性基因组调节元件控制的基因表达的变化。虽然 我们和其他人已经确定监管元素是人类特异性进化的突出底物 变化，尸体后人类和非人类灵长类动物大脑的最新地图忽略了这种动态刺激 响应迅速的监管要素。没有培训与上下文相关数据的培训，当前的计算模型 推断基于序列的调节功能无法预测活动依赖性调节元件。我们 假设人类发散活性调节的元素（HDARES）发生了遗传变化 并且我们可以使用全基因组发现这些可塑性的人类特异性遗传基础 方法。我们将使用实验和计算方法来预测和比较活动调节 人类神经元与恒河猴和黑猩猩的神经元的反应。我们已经发展了 创新的模型系统将使我们能够刺激以前无法访问的生理活动状态 灵长类动物神经元，机器学习模型，以根据序列预测调节功能 并行的记者测定和CRISPRI分析，使我们能够评估候选HDARES的功能。 通过成功完成这些研究，我们将确定哪些基因组元素和遗传 变化是人类神经元中活动依赖性反应以及这些反应的变化程度 元素代表了人类谱系进化选择的主要底物。这将奠定基础 为了进一步的表型表征，人类大脑中细胞可塑性机制。 此外，这些数据集将为剖析遗传机制提供宝贵的资源 神经发育障碍。