Single-nuclei Multi-Omics Alzheimer's disease

Single-nuclei epigenomic and transcriptomic landscape in Alzheimer's disease

The gene regulatory landscape of the brain is highly dynamic in health and disease, coordinating a menagerie of biological processes across distinct cell-types and cell states. Fully contextualizing molecular signatures of disease with respect to specific cell-types requires a holistic multi-layered experimental and analytical approach. While single-cell transcriptomics has been used extensively in human disease systems, very few single-cell epigenomic studies have been carried out in primary disease samples. Here, we present a multi-omic single-cell study of 191,897 nuclei in late-stage Alzheimer’s Disease (AD), in which we profiled chromatin accessibility and gene expression in the same biological samples, uncovering vast glial heterogeneity in late-stage AD. We describe cis-regulatory relationships in specific cell-types at AD risk loci defined by genome wide association studies (GWAS), demonstrating the utility of this multi-omic single-cell framework for uncovering disease and cell-type-specific regulatory mechanisms. Trajectory analysis of glial populations displayed dynamic transcription factor regulatory patterns in the transition between healthy and diseased states. Further, we introduce scWGCNA, a co-expression network analysis strategy robust to the sparsity of single-cell data, to perform a systems-level meta-analysis of AD transcriptomics. Finally, this work is highly accessible through our intuitive web-portal, allowing for straightforward interrogation of this multi-omic dataset.. A shiny app has been generated to easily visualize the data. Visit AD Single-nuclei Multi-Omics Shiny App here