Mathematical, Computational and Systems Biology (MCSB) Program, University of California, Irvine, CA, USA.
Institute for Memory Impairments and Neurological Disorders (MIND), University of California, Irvine, CA, USA.
Nat Genet. 2021 Aug;53(8):1143-1155. doi: 10.1038/s41588-021-00894-z. Epub 2021 Jul 8.
The gene-regulatory landscape of the brain is highly dynamic in health and disease, coordinating a menagerie of biological processes across distinct cell types. Here, we present a multi-omic single-nucleus study of 191,890 nuclei in late-stage Alzheimer's disease (AD), accessible through our web portal, profiling chromatin accessibility and gene expression in the same biological samples and uncovering vast cellular heterogeneity. We identified cell-type-specific, disease-associated candidate cis-regulatory elements and their candidate target genes, including an oligodendrocyte-associated regulatory module containing links to APOE and CLU. We describe cis-regulatory relationships in specific cell types at a subset of AD risk loci defined by genome-wide association studies, demonstrating the utility of this multi-omic single-nucleus approach. Trajectory analysis of glial populations identified disease-relevant transcription factors, such as SREBF1, and their regulatory targets. Finally, we introduce single-nucleus consensus weighted gene coexpression analysis, a coexpression network analysis strategy robust to sparse single-cell data, and perform a systems-level analysis of the AD transcriptome.
大脑的基因调控景观在健康和疾病中具有高度动态性，协调着不同细胞类型之间的一系列生物过程。在这里，我们通过我们的网络门户展示了一项针对晚期阿尔茨海默病（AD）的 191,890 个核的多组学单细胞研究，对同一生物样本中的染色质可及性和基因表达进行了分析，并揭示了巨大的细胞异质性。我们鉴定了细胞类型特异性的、与疾病相关的候选顺式调控元件及其候选靶基因，包括与 APOE 和 CLU 相关的少突胶质细胞相关调控模块。我们描述了特定细胞类型在全基因组关联研究定义的 AD 风险位点子集上的顺式调控关系，证明了这种多组学单细胞方法的实用性。神经胶质群体的轨迹分析确定了疾病相关的转录因子，如 SREBF1，及其调控靶基因。最后，我们引入了单细胞共识加权基因共表达分析，这是一种对稀疏单细胞数据具有鲁棒性的共表达网络分析策略，并对 AD 转录组进行了系统水平的分析。
