Age‐Associated Transcriptomic and Epigenetic Alterations in Mouse Hippocampus

ABSTRACT Aging represents a major risk for human neurodegenerative disorders, such as dementia and Alzheimer's disease, and is associated with a functional decline in neurons and impaired synaptic plasticity, leading to a gradual decline in memory. Previous research has identified molecular and functional changes associated with aging through transcriptomic studies and neuronal excitability measurements, while the role of chromatin‐level regulation in vulnerability to aging‐related diseases is not well understood. Moreover, the causal relationship between molecular alterations and aging‐associated decline in functions of different cell types remains poorly understood. Here, we systematically characterized gene regulatory networks in a cell type‐specific manner in the aging mouse hippocampus, a central brain region involved in learning and memory formation, by simultaneously profiling gene expression and chromatin accessibility at a single‐nucleus level. The analysis of multiome (RNA and ATAC) sequencing recapitulated the diversity of glial and neuronal cell types in the hippocampus and revealed transcriptomic and chromatin accessibility level changes in different cell types, among which oligodendrocytes and dentate gyrus (DG) neurons exhibited the most drastic changes. We found pronounced aging‐dependent chromatin‐level changes among neurons, especially for genes related to synaptic plasticity. Our data suggest that BACH2, a candidate transcription factor implicated in aging‐mediated functional decline of DG neurons, potentially regulates genes associated with synaptic plasticity, cell death, and inflammation during aging. Taken together, our single‐nucleus multiome analysis reveals potential cell type‐specific regulators involved in the aging of neurons and glial cells.