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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

基本信息

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
项目类别：
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

项目摘要

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.

项目总结