Modeling gene regulatory mechanisms contributing to the evolution of the human cerebral cortex

模拟促进人类大脑皮层进化的基因调控机制

• 批准号: 10683962
• 负责人: Mary Baumgartner
• 金额: $ 7.38万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10683962
• 关键词: Acceleration; Address; Adult; Affect; Binding; Bioinformatics; Brain; Cell Count; Cell Culture Techniques; Cell Cycle; Cells; Cerebral cortex; Cerebrum; ChIP-seq; Chromatin; Clinical; Cognition; Comparative Study; Complement; Data; Development; Developmental Delay Disorders; Developmental Gene; Disease; Embryo; Enhancers; Epigenetic Process; Etiology; Event; Evolution; Exhibits; Fellowship; Foundations; Gene Expression; Gene Expression Regulation; Genes; Genetic; Genetic Transcription; Genome; Goals; Growth; Heterogeneity; Higher Order Chromatin Structure; Histologic; Human; Human Genetics; Impaired cognition; Kinetics; Knockout Mice; Knowledge; Length; Link; Mediating; Methods; Modeling; Molecular; Morphology; Mus; Mutation; Neurobiology; Neurodevelopmental Disorder; Neuroglia; Neurons; Organoids; Orthologous Gene; Pan Genus; Phenotype; Primates; Production; Proliferating; Quantitative Reverse Transcriptase PCR; Radial; Regulation; Regulator Genes; Regulatory Element; Reporting; Repression; Research; Resolution; Role; Shapes; Speed; Variant; Work; autism spectrum disorder; cell behavior; cell type; chromosome conformation capture; epigenetic profiling; fetal; functional genomics; gene network; gene regulatory network; genome-wide; histone modification; human fetal brain; humanized mouse; in vivo; innovation; mouse model; nerve stem cell; neural; neurogenesis; novel; overexpression; programs; recruit; risk variant; stem cell proliferation; stem cells; success; transcription factor; transcriptomics

Project Summary The vast expansion of the human cerebral cortex distinguishes us from our primate relatives, and this cortical expansion is the foundation of uniquely human higher-order cognition. Numerous developmental innovations, such as increased proliferation of cortical progenitor cells, contributed to this cortical growth. Ultimately, these developmental innovations arose from genetic changes in the human lineage, which altered the molecular and cellular programs underpinning development. Understanding the gene regulatory networks that specifically inform human cortical development and cortical size is crucial for understanding the etiology of neurodevelopmental disorders, which often present with cognitive impairment. Efforts to identify human-specific genetic changes have revealed Human Accelerated Regions (HARs), which are highly conserved regulatory elements that exhibit a high rate of human-specific sequence change. A growing body of evidence implicates HARs in cortical development and evolution. In particular, the HAR HACNS205 has (i) human-biased accessibility in cerebral organoids, compared to chimpanzee, and evidence of enhancer activity; (ii) an essential role in human neural stem cell proliferation; and (iii) a known target gene in the fetal human cortex, BRN2, a transcription factor that regulates corticogenesis and has human-biased expression in cortical progenitor cells relative to chimp. BRN2 is an autism risk gene, and its target genes display enrichment for autism risk genes. In addition, clinical work has linked BRN2 mutations to global developmental delay and cognitive impairment. BRN2 has also recently been implicated in human cortical evolution. Overexpression studies indicate BRN2 is important for designating neural progenitor cell identity, the timing of neurogenesis, and the production of specific neuronal subtypes. However, the role of HACNS205 in human cortical development is not clear; moreover, the role of BRN2 in early cortical development has not been reported. The goal of this proposal is to address these gaps in the field, by using a humanized mouse model to study how HACNS205 impacts BRN2 expression levels and BRN2 transcription factor binding, and how these primary molecular effects shape gene expression, molecular networks, progenitor cell behavior, and the timing of key events in cortical development. Specifically, I will employ genome-wide epigenetic and single-cell transcriptomic analyses of embryonic cortical development. These results will then be leveraged to perform targeted phenotypic analysis of the developing cortex in these mice, to identify HACNS205-driven shifts in progenitor cell behavior, neurogenesis, and ultimately cortical morphology. The applicant’s long-term goal is to study the emergence of novel cell types in brain evolution. This fellowship will aid the applicant in developing the expertise in bioinformatics and evolutionary, regulatory, and functional genomics that will greatly bolster her success in this line of research, complementing her current expertise in neurobiology and cortical development.

项目摘要 人类大脑皮层的广泛扩展使我们与我们的主要亲戚区分开 扩展是独特的人类高阶认知的基础。许多发展创新， 例如，皮质祖细胞的增殖增加，导致了这种皮质生长。最终，这些 发展创新是由人类谱系的遗传变化引起的，这改变了分子和 基于开发的蜂窝计划。了解特定的基因调节网络 告知人类皮质发育和皮质规模对于理解病因至关重要 神经发育障碍，通常会出现认知障碍。识别特定人类的努力 遗传变化揭示了人类加速区域（HAR），这些区域是高度保守的调节 存在较高的人类特异性序列变化的元素。越来越多的证据暗示 皮质发育和进化中的苛刻。特别是，HACNS205具有（i）人为偏见 与黑猩猩相比，大脑器官的可及性和增强剂活性的证据； （ii）必不可少的 在人类神经干细胞增殖中的作用； （iii）胎儿人皮层中的已知靶基因，brn2，a 调节皮质生成并在皮质祖细胞中具有人类偏见的转录因子 相对于黑猩猩。 BRN2是一种自闭症风险基因，其靶基因显示自闭症风险基因的富集。 此外，临床工作将BRN2突变与全球发育延迟和认知障碍联系起来。 BRN2最近也与人类皮质进化有关。过表达研究表明BRN2是 对于设计神经元祖细胞身份，神经发生的时间和特定的产生至关重要 神经元亚型。但是，HACNS205在人类皮质发育中的作用尚不清楚。而且， 尚未报道BRN2在早期皮质发育中的作用。该提议的目的是解决这些问题 通过使用人源化的小鼠模型研究HACNS205如何影响BRN2表达水平，该领域的间隙 和BRN2转录因子结合，以及这些主要分子如何影响基因表达， 分子网络，祖细胞行为以及皮质发育中关键事件的时机。具体来说， 我将采用胚胎皮质发育的全基因组表观遗传学和单细胞转录组分析。 然后，将利用这些结果来对其中发育中的皮质进行针对性的表型分析 小鼠，鉴定祖细胞行为，神经发生和最终皮质的HACNS205驱动的变化 形态学。申请人的长期目标是研究大脑进化中新型细胞类型的出现。这 奖学金将有助于申请人发展生物信息学和进化，监管的专业知识 功能性基因组学将在这一研究中极大地增强她的成功，完成她的当前 神经生物学和皮质发展方面的专业知识。