Single-cell Epigenome Analysis of the Alzheimer's Disease Brain

标题：阿尔茨海默病脑的单细胞表观基因组分析（PI：Hartl） 阿尔茨海默病（AD）影响了600多万美国人，但没有治愈方法，也很少有有效的治疗方法 都是可用的。全基因组关联研究（GWAS）发现了数千个分离突变 这会显著增加AD风险。这些变异大多改变了非蛋白质编码序列， 功能注释，阻碍将风险赋予突变转化为治疗或预防性突变的努力 治疗遗传力分区表明，这些变异可能扰乱神经胶质细胞中的基因表达 （特别是小胶质细胞），最终导致AD病理学。将这些变异及其下游效应联系起来 - 由于缺乏顺式调控元件图谱， 这些主要的神经胶质细胞类别及其亚型。拟议的研究解决了这一关键的知识差距， 将尖端的单细胞多组学技术应用于死后人脑样本， 表型正常的供体和AD患者。具体来说，染色质可及性或组蛋白修饰 将与背外侧前额叶皮层（DLPFC）中单细胞分辨率的基因表达联合询问 从多个供体，以确定和表征细胞类型特异性基因调控元件， 异常的细胞状态和疾病相关的细胞反应在人类AD大脑。单细胞染色质状态 将来自表型正常个体的基因表达图谱与来自AD受试者的基因表达图谱进行比较 确定脑细胞类型，基因和调控元件，表现出显着的病理变化， 条件最后，新生成的细胞类型解析表观基因组图谱将与公共 基因组资源，以提供AD风险变体的功能注释，鉴定疾病相关细胞类型， 优先考虑基因、转录因子和分子通路，以便将来进行机理研究。结果 这项研究将为研究AD的发病机制和开发改良的 AD治疗

Title: Single-cell Epigenome Analysis of the Alzheimer’s Disease Brain (PI: Hartl) Alzheimer’s disease (AD) affects more than 6 million American but no cures and few effective treatments are available. Genome-wide association studies (GWAS) have uncovered thousands of segregating mutations that significantly increase AD risk. Most of these variants alter non-protein-coding sequence and lack clear functional annotation, hindering efforts to translate risk-conferring mutations into curative or preventative therapies. Heritability partitioning suggests that these variants likely perturb gene expression in glial cells (especially microglia), ultimately leading to AD pathology. Linking these variants – and their downstream effects – to specific regulatory networks and pathways has been hindered by a lack of cis-regulatory element maps for these major glial cell classes and their subtypes. The proposed study addresses this critical knowledge gap by applying a cutting-edge single cell multi-omic technology to postmortem human brain samples from phenotypically normal donors and AD patients. Specifically, the chromatin accessibility or histone modifications will be interrogated jointly with gene expression at single cell resolution in dorsolateral prefrontal cortex (DLPFC) from multiple donors, to identify and characterize the cell-type-specific gene regulatory elements that drive aberrant cell states and disease-relevant cellular responses in human AD brains. The single cell chromatin state and gene expression atlases from phenotypically normal individuals will be compared to those from AD subjects to determine the brain cell types, genes and regulatory elements that exhibit significant changes in pathological conditions. Finally, the newly generated cell-type resolved epigenome maps will be integrated with public genomic resources to provide functional annotation of the AD risk variants, identify disease-relevant cell types, prioritize genes, transcription factors, and molecular pathways for future mechanistic investigation. Results of the proposed study will provide a much-needed tool for study of AD pathogenesis and development of improved AD therapies.