Maria Luisa Amaral, Sainath Mamde, Michael Miller, Xiaomeng Hou, Jessica Arzavala, Julia Osteen, Nicholas D. Johnson, Elizabeth W. Smoot, Qian Yang, Emily Eisner, Qiurui Zeng, Cindy Tatiana Báez-Becerra, Jacqueline Olness, Joseph Colin Kern, Jonathan Rink, Ariana Barcoma, Silvia Cho, Stella Maris Cao, Nora Emerson, Jasper Lee, Jackson Willier, Timothy Loe, Henry Jiao, Songpeng Zu, Quan Zhu, Sebastian Preissl, Allen Wang, Joseph R. Ecker, M. Margarita Behrens, Bing Ren
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.