Aging Differentially Alters the Transcriptome and Landscape of Chromatin Accessibility in the Male and Female Mouse Hippocampus

Author:

Achiro Jennifer M.ORCID,Tao YangORCID,Gao FuyingORCID,Lin Chia-Ho,Watanabe Marika,Neumann SylviaORCID,Coppola GiovanniORCID,Black Douglas L.ORCID,Martin Kelsey C.ORCID

Abstract

AbstractAging-related memory impairment and pathological memory disorders such as Alzheimer’s disease differ between males and females, and yet little is known about how aging-related changes in the transcriptome and chromatin environment differ 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 in 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 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 function. Aging was associated with increased chromatin accessibility in both male and female hippocampus, especially in repetitive elements, and with an increase in LINE-1 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. Sex differences in gene expression and chromatin accessibility were amplified with aging, findings that may shed light on sex differences in aging-related and pathological memory loss.HighlightsAging amplifies sex differences in the transcriptome and chromatin accessibility of mouse hippocampusAging is associated with widespread changes in the transcriptome of mouse hippocampus, including in genes involved in immune response and synaptic functionMyelin sheath-related genes in aged hippocampus show female-biased expressionAlternative splicing of myelin sheath-related genes changes with aging in the hippocampusSex-bias is evident in alternative splicing of nuclear and primary cilia genesAging in the hippocampus is associated with increased chromatin accessibility in both males and femalesLINE-1 derived sequences are more accessible and LINE-1 transcripts are upregulated in the aged hippocampus of both males and femalesPromoter and CpG-rich regions show male-biased accessibility

Publisher

Cold Spring Harbor Laboratory

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