Single-Cell Multi-Omic Profiling of Chromatin and Transcriptome in Aging Brain Tissue
DOI:
https://doi.org/10.5281/zenodo.22757178Keywords:
brain aging, single-nucleus multiome, chromatin accessibility, microglia activation, transcription factor motif, neuroinflammationAbstract
Brain aging is accompanied by cell type-specific changes in gene expression and chromatin state that bulk tissue
profiling cannot resolve, and the transcription factor programmes driving these changes across individual neuronal
and glial populations remain incompletely mapped. Here we applied joint single-nucleus RNA and ATAC
sequencing (10x Multiome) to cortical and hippocampal tissue from young (3-month) and aged (24-month) mice to
profile cell type-resolved chromatin accessibility and transcriptional change across brain aging. Clustering identified
14 major cell types, and differential accessibility analysis showed that microglia exhibited the largest number of
age-related accessibility changes of any cell type, with a strong gain of accessibility at loci encoding
pro-inflammatory and phagocytic genes. Chromatin variability analysis of transcription factor motifs (chromVAR)
identified increased NF-kB and PU.1 motif accessibility specifically in aged microglia, closely tracking increased
expression of their target genes, while these same motifs showed no significant accessibility change in neurons or
astrocytes from the same tissue. Neurons showed a smaller but significant set of age-related accessibility changes
concentrated at synaptic and neuronal identity genes, with a directional bias toward loss of accessibility, and this
neuronal accessibility loss correlated at the single-cell level with reduced expression of the same genes within
individual aged neurons. Cross-cell-type comparison showed minimal overlap between the accessibility changes
defining aged microglia and aged neurons, indicating that brain aging engages substantially distinct chromatin
remodeling programmes in different cell types rather than a shared, tissue-wide ageing signature. These results
provide a cell type-resolved chromatin accessibility map of brain aging and identify NF-kB/PU.1-driven microglial
activation and synaptic gene silencing in neurons as the two dominant, largely independent chromatin remodeling
programmes underlying the aged brain phenotype.
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