Single-cell epigenomics uncovers heterochromatin instability and transcription factor dysfunction during mouse brain aging

The mechanisms regulating transcriptional changes during brain aging remain poorly understood. Here, we use single-cell epigenomics to profile chromatin accessibility and gene expression across eight mouse brain regions at 2, 9, and 18 months of age. In addition to a marked decline in progenitor populations involved in neurogenesis and myelination, we observe widespread and concordant age-associated changes in transcription and chromatin accessibility across both neuronal and glial cell types. These alterations are accompanied by dysregulation of master transcription factors and a shift toward stress-response programs driven by activator protein 1 (AP-1), indicating progressive drift in cellular identity with aging. We further identify region- and cell-type-specific heterochromatin loss, characterized by increased accessibility at H3K9me3-marked domains, activation of transposable elements, and upregulation of long noncoding RNAs, particularly in glutamatergic neurons. Together, these findings reveal age-related disruption of heterochromatin maintenance and transcriptional regulation, highlighting vulnerable brain regions, cell types, and molecular pathways in brain aging.