Single‐cell network biology characterizes cell type gene regulation for drug repurposing and phenotype prediction in Alzheimer’s disease

Abstract

AbstractBackgroundDysregulation of gene expression in Alzheimer’s disease (AD) remains elusive, especially at the cell type level. Gene regulatory network, a key molecular mechanism linking transcription factors (TFs) and regulatory elements to govern target gene expression, can change across cell types in the human brain and thus serve as a model for studying gene dysregulation in AD. However, it is still challenging to understand how cell type networks work abnormally under AD.MethodTo address this, we integrated single‐cell multi‐omics data and predicted the gene regulatory networks in AD and control for four major cell types, excitatory and inhibitory neurons, microglia and oligodendrocytes. Importantly, we applied network biology approaches to analyze the changes of network characteristics across these cell types, and between AD and control.ResultWe found that many hub TFs target different genes between AD and control (rewiring). Also, these cell‐type gene networks show strong hierarchical structures in which top TFs (master regulators) are largely common across cell types, whereas different TFs operate at the middle levels in some cell types (e.g., microglia). The regulatory logics of enriched network motifs (e.g., feed‐forward loops) further uncover cell‐type‐specific TF‐TF cooperativities in gene regulation. The cell type networks are highly modular. Several network modules with cell‐type‐specific expression changes in AD pathology are enriched with AD‐risk genes and putative targets of approved and pending AD drugs, suggesting possible cell‐type genomic medicine in AD. Finally, using the cell type gene regulatory networks, we developed machine learning models to classify and prioritize additional AD genes. We found that top prioritized genes predict AD and clinical phenotypes (e.g., cognitive impairment).ConclusionOverall, this single‐cell network biology analysis provides a comprehensive map linking genes, regulatory networks, cell types and drug targets and reveals mechanisms on cell‐type gene dysregulation in AD.