Aging Differentially Alters the Transcriptome and Landscape of Chromatin Accessibility in the Male and Female Mouse Hippocampus [ATAC-Seq]
Long-term memory formation is dependent on gene expression changes in the hippocampal region of the brain. Aging-related memory impairments and incidence of pathological memory disorders such as Alzheimer's disease differ between males and females, and yet little is known about how aging-related changes to the transcriptome and chromatin environment differs between sexes in the hippocampus. To investigate this question, we compared the chromatin accessibility landscape and gene expression/alternative splicing pattern of young adult and aged mouse hippocampus of both males and females using ATAC-seq and RNA-seq. We detected significant aging-dependent changes in the expression of genes involved in immune response, cell adhesion, and synaptic function, and aging-dependent changes in the alternative splicing of myelin sheath genes. We found significant sex-bias in the expression and alternative splicing of hundreds of genes, including aging-dependent female-biased expression of myelin sheath genes and aging-dependent male-biased expression of genes involved in synaptic activity. Aging was associated with increased chromatin accessibility in both male and female hippocampus, especially in repetitive elements, and with an increase in LINE1 transcription. We detected significant sex-bias in chromatin accessibility in both autosomes and the X chromosome, with male-biased accessibility enriched at promoters and CpG-rich regions. Overall, sex differences in both gene expression and chromatin accessibility were amplified with aging, revealing that although some aspects of hippocampal aging are sex-independent, underlying sex differences in gene expression and chromatin dynamics in aging may shed light on sex differences in aging-related and pathological memory loss. Overall design: ATAC-Seq from hippocampus of young adult (10 week) or aged (80 week) male and female mice. Six biological replicates for young adult male, 7 biological replicates for aged adult male, 8 biological replicates each for young and aged female, for a total of 29 samples.