Cell-type-specific chromatin accessibility patterns in aging hippocampal neural stem cells reveal MEF2 family motif enrichment

The mammalian brain continues to generate new neurons throughout life. This regenerative potential is dependent on neural stem cell pools and declines with age or in neurodegenerative diseases, contributing to memory impairment and cognitive decline. Although epigenetic remodeling has been implicated in neural stem cell aging, transcriptional features associated with this process remain incompletely characterized. Previously generated publicly available ATAC (Assay for Transposase-Accessible Chromatin)-seq datasets were analyzed to identify age-associated chromatin accessibility patterns in hippocampal neural stem cells. Using peak presence-based comparisons, genomic regions were identified as accessible in older samples but not in younger counterparts under consistent peak-calling thresholds. Motif enrichment analysis of these regions revealed overrepresentation of MEF2 family binding motifs alongside reduced representation of motifs associated with neurogenic transcription factors. Complementary analysis of independent gene expression datasets showed increased MEF2C transcript levels in aged hippocampal neural stem cells. An exploratory in vitro overexpression assay in a human neural progenitor-like cell line revealed altered cell morphology and reduced cell-cell contact. Importantly, the MEF2-family motif enrichment was observed selectively in hippocampal neural stem cell peak sets and was not detected in whole hippocampal tissue or subventricular zone neural stem cell datasets, demonstrating that aging-associated chromatin features are strongly cell-type dependent. Together, these findings identify MEF2C as a candidate gene associated with aging-related chromatin features in hippocampal neural stem cells and generate hypotheses for future functional studies.