UC San Diego

Aging is accompanied by widespread epigenomic and transcriptional alterations that influence cellular function. In the brain, these changes contribute to cognitive decline and increased susceptibility to neurodegenerative diseases. However, the mechanisms driving transcriptional dysregulation in distinct neuronal and glial populations remain poorly understood. In this dissertation, I analyze single-cell multi-omics data to elucidate the epigenetic signatures of aging in the mouse brain, focusing on chromatin accessibility, transcription factor activity, and heterochromatin stability. In Chapter 1, we profile chromatin accessibility, H3K9me3-marked heterochromatin, and gene expression across 5 tissues in aging mice. We identify age-associated differentially accessible regulatory elements in diverse cell types and reveal that excitatory neurons exhibit significant heterochromatin destabilization, characterized by increased accessibility at typically repressed regions. This breakdown of repressive chromatin architecture drives aberrant gene expression and transposable element activation, suggesting a mechanistic link between heterochromatin loss and age-related genomic instability. In Chapter 2, we extend this analysis, using single-cell multi-omics to integrate chromatin accessibility, gene expression, and spatial information. We expand our scope to include both male and female mice and eight different brain regions, generating the most comprehensive chromatin accessibility atlas of mammalian brain aging to date. We find that aging is associated with a loss of progenitor populations, dysregulation of master transcription factors, and AP-1-mediated stress. Finally, we observe brain-region specific heterochromatin destabilization, transposable element activation, and dysregulation of long non-coding RNAs. These findings present a detailed view of age-related chromatin and transcriptional alterations in the brain, highlighting key regulatory shifts that reshape gene expression across different cell types. By mapping these changes at single-cell resolution, this work provides a valuable resource for investigating the molecular underpinnings of brain aging and its potential contributions to cognitive decline and neurodegenerative processes.