Single nucleus multiomics identifies ZEB1 and MAFB as candidate regulators of Alzheimer’s disease-specific cis regulatory elements
Cell type-specific transcriptional differences between brain tissues from donors with Alzheimer’s Disease (AD) and unaffected controls have been well-documented, but few studies have rigorously interrogated the regulatory mechanisms responsible for these alterations. We performed single cell multiomics (RNA-seq+ATAC-seq) on 105,332 nuclei isolated from cortical tissues from 7 AD and 8 unaffected donors to identify candidate cis-regulatory elements (CREs) involved in AD-associated transcriptional changes. We detected 319,861 significant correlations, or links, between gene expression and cell-type specific transposase accessible regions that are enriched for active CREs. Among these, 40,831 were unique to AD tissues. Validation experiments confirmed the activity of many regions, including several candidate regulators of APP expression. We identified ZEB1 and MAFB as transcription factors playing important roles in AD-specific gene regulation in neurons and microglia, respectively. Links were globally enriched for heritability of AD risk, specifically in microglia, and previously identified active regulatory regions.
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Additional pre-processing scripts can be found in the scripts directory. This includes scripts for sample demultiplexing using cellSNP and vireo, plotting functions, and LDSC.