Single‐cell multi‐omics analysis identifies dynamic regulation of SREBF1 in Alzheimer’s disease

Abstract

The gene-regulatory landscape of the brain is highly dynamic in health and disease, coordinating a menagerie of biological processes across distinct cell-types. Understanding these regulatory programs requires a holistic experimental and analytical approach, especially in understanding neurodegenerative disorders such as Alzheimer's Disease (AD).In this study, we used single-nucleus ATAC-seq (snATAC-seq) to profile the epigenome in all major cell types of the human brain in AD, and we single-nucleus RNA-seq (snRNA-seq) in the same biological samples, together painting a more complete portrait of the changes brought on by disease. We constructed an oligodendrocyte trajectory using 58,221 single-nuclei chromatin profiles and 36,773 single-nuclei transcriptomes. We developed a new analysis approach, scWGCNA, a method for interrogation of cell population-specific co-expression networks.We investigated the dynamics of transcription factor (TF) binding motifs throughout the oligodendrocyte trajectory, and evaluated chromatin accessibility, TF motif enrichment, gene expression, and cis-regulatory elements to identify SREBF1, a master regulator of cholesterol biosynthesis and myelination, downregulated in late-stage AD in oligodendrocytes. We extend our analysis of SREBF1 in oligodendrocytes by examining its downstream regulatory targets in the context of gene co-expression networks. Notably, we found several oligodendrocyte modules significantly enriched for targets of SREBF1, indicating the importance of SREBF1 in regulating gene expression in these modules. Using a multi-scale dataset of bulk-tissue RNA-seq, high-throughput proteomics, and SREBF1 ChIP-seq data (ENCODE), we defined a protein-protein interaction (PPI) network of SREBF1 target genes. Additionally, we found module eigengene expression of SREBF1 targets downregulated in early- and late-pathology AD cases at the level of proteins and RNA, corroborated by downregulation of SREBF1 activity in snATAC-seq data.Altogether, our data and analyses highlight key biological role of SREBF1 in AD biology. While the causative molecular mechanisms of sporadic AD remain unknown, our work is an important stepping stone in fully unraveling the nature of gene regulation in AD, especially in regards to genomic loci with well-described heritable disease risk. Additional work is needed to spatially resolve the complexity of single-cell gene expression and epigenomics in AD and neurodegeneration, in general.