Single-cell epigenomic roadmap of Alzheimer's disease

阿尔茨海默病的单细胞表观基因组路线图

• 批准号: 10390136
• 负责人: Samuel Joseph Morabito
• 金额: $ 4.19万
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 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 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10390136
• 关键词: Affect; Age; Alzheimer' s Disease; Alzheimer' s disease brain; Alzheimer' s disease patient; Alzheimer' s disease risk; Amyloid beta-Protein; Atlases; Axon; Binding; Biological; Biological Assay; Biology; Brain; Brain region; CRISPR/Cas technology; Cell Nucleus; Cells; Chromatin; Cognitive; Communities; Complex; Consensus; Critical Pathways; Data; Data Set; Development; Disease; Disease associated microglia; Disease susceptibility; Distal Enhancer Elements; Enhancers; Environmental Risk Factor; Evaluation; Future; Gene Expression; Genes; Genetic Enhancer Element; Genetic Risk; Genetic Variation; Genomic Segment; Gliosis; Health; Heritability; Heterogeneity; High-Throughput Nucleotide Sequencing; Hippocampus (Brain); Impaired cognition; Knock-out; Link; Memory Loss; Meta-Analysis; Methods; Microglia; Molecular; Nerve Degeneration; Neurodegenerative Disorders; Neuroglia; Neurons; Pathology; Pathway Analysis; Pathway interactions; Pattern; Phenotype; Population; Prefrontal Cortex; Publishing; Regulator Genes; Regulatory Element; Resolution; Resources; Risk; Risk Factors; Role; Senile Plaques; Small Nuclear RNA; Specificity; Structure; Supervision; System; TREM2 gene; Techniques; Therapeutic; Transposase; Untranslated RNA; Validation; Variant; Work; brain cell; cell type; deep learning; disorder risk; entorhinal cortex; epigenome; epigenomics; experimental study; gene interaction; gene network; genetic risk factor; genetic variant; genome wide association study; healthy aging; human disease; induced pluripotent stem cell; mind control; molecular phenotype; multimodality; promoter; risk variant; single cell analysis; tau aggregation; trait; transcription factor; transcriptome; transcriptome sequencing; transcriptomics

Project Summary/Abstract Genetic variation drives phenotypic variation across many traits, including heritable risk for disease susceptibility in neurodegenerative disorders such as Alzheimer’s Disease (AD). For complex polygenic human diseases, it is difficult to unravel precisely which molecular changes are brought on by genetic risk factors. It is well known that genetic variants at the APOE locus can confer a neuroprotective status from AD, while another variant drastically increases one’s chances of developing disease. Even these well studied variants are not fully understood at the molecular level. The majority of disease-associated risk variants for AD and other disorders lie in non-coding regulatory elements and are therefore best studied using epigenomic techniques. Since previous studies have shown that AD affects different brain regions and cell types throughout its progression, I hypothesize that the mechanisms underlying genetic risk for AD act similarly in a progressive, region-specific, and cell-type-specific manner. In this proposal, we aim to generate chromatin accessibility profiles for single cells across the prefrontal cortex, the hippocampus, and the entorhinal cortex of AD patient brains, and integrate with published single cell transcriptomics data, thereby allowing us to identify enhancer- gene interactions that are disrupted by AD risk variants. Our preliminary work has shown that microglia-specific enhancers are enriched for AD genetic risk factors. Therefore, we will use CRISPR-cas9 to delete an enhancer linked to the variant rs4663105 at the BIN1 locus in induced pluripotent stem cell (iPSC) derived microglia, thereby allowing us to unravel its role in the regulatory landscape. My preliminary data from the prefrontal cortex shows that the chromatin accessibility landscape is highly cell-type specific and is significantly altered in AD patient brains, and I expect that we will find regional specificity of regulatory elements that are disrupted by AD risk variants. Aside from our specific task of identifying these disease-associated regulatory elements, an integrated study of single-cell epigenomics and single-cell transcriptomics data in AD brains will be of great value to the broader AD community to further implicate genes, networks, and pathways as targets for future studies.

项目摘要/摘要 遗传变异驱动了许多特征的表型变异，包括疾病的可遗传风险 神经退行性疾病（例如阿尔茨海默氏病）（AD）的敏感性。对于复杂的多基因人 疾病，很难精确地阐明遗传危险因素带来哪些分子变化。这是 众所周知，APOE基因座的遗传变异可以与AD相连，而另一个 变体大大增加了一个人发展疾病的机会。即使是这些研究良好的变体也不是 在分子水平上充分理解。大多数与疾病相关的AD和其他风险变异 疾病位于非编码调节元件中，因此使用表观基因组技术是最好的研究。 由于以前的研究表明，AD会影响其整个整个大脑区域和细胞类型 进展，我假设AD的遗传风险的基础机制在渐进性， 区域特异性和细胞类型特异性方式。在此建议中，我们旨在生成染色质可及性 跨额叶皮层，海马和AD患者内嗅皮层的单个细胞的轮廓 大脑，并与已发表的单细胞转录组学数据集成，从而使我们能够识别增强子 - 受AD风险变体破坏的基因相互作用。我们的初步工作表明小胶质细胞特异性 增强子富含AD遗传危险因素。因此，我们将使用CRISPR-CAS9删除增强器 与诱导多能干细胞（IPSC）衍生的小胶质细胞中BIN1基因座的变体RS4663105相关联， 从而使我们能够揭开其在监管景观中的作用。我的初步数据来自前额叶 皮层表明，染色质的可及性景观是高度特异性的，并且在 广告患者的大脑，我希望我们会发现被破坏的监管要素的区域特异性 广告风险变体。除了我们确定这些疾病相关的调节元素的具体任务外， 广告大脑中单细胞表观基因组学和单细胞转录组数据的综合研究将非常重要 对更广泛的广告社区的价值，以进一步将基因，网络和途径视为未来的目标 研究。