Abstract
Summary DNA methylation is a central regulator of genome function, and altered methylation patterns are indicative of biological aging and mortality. Age‐related cellular, biochemical, and molecular changes in the hippocampus lead to cognitive impairments and greater vulnerability to neurodegenerative disease that varies between the sexes. The role of hippocampal epigenomic changes with aging in these processes is unknown as no genome‐wide analyses of age‐related methylation changes have considered the factor of sex in a controlled animal model. High‐depth, genome‐wide bisulfite sequencing of young (3 month) and old (24 month) male and female mouse hippocampus revealed that while total genomic methylation amounts did not change with aging, specific sites in CG and non‐CG (CH) contexts demonstrated age‐related increases or decreases in methylation that were predominantly sexually divergent. Differential methylation with age for both CG and CH sites was enriched in intergenic and intronic regions and under‐represented in promoters, CG islands, and specific enhancer regions in both sexes, suggesting that certain genomic elements are especially labile with aging, even if the exact genomic loci altered are predominantly sex‐specific. Lifelong sex differences in autosomal methylation at CG and CH sites were also observed. The lack of genome‐wide hypomethylation, sexually divergent aging response, and autosomal sex differences at CG sites was confirmed in human data. These data reveal sex as a previously unappreciated central factor of hippocampal epigenomic changes with aging. In total, these data demonstrate an intricate regulation of DNA methylation with aging by sex, cytosine context, genomic location, and methylation level.
Highlights
Direct DNA base modifications, such as cytosine methylation, are proposed to fundamentally regulate the mammalian genome through altering genome accessibility (Law & Jacobsen 2010)
DNA methylation was quantified in a base-specific manner across promoters, CG Islands and associated flanking regions, and gene regulatory regions from the hippocampus of male and female young (3 months) and old (24 months) C57BL6 mice using bisulfite oligonucleotide-capture sequencing (BOCS), a method we have quantitatively validated (Masser et al 2016)
DNA methylation was quantified in a base-specific manner across almost all annotated promoters and CG Island units [Island, shore (±2 kb from island), and shelf (±2 kb from shores)] for a total of 109Mb of coverage using bisulfite-oligonucleotide capture sequencing (BOCS, Figure S2A-B)
Summary
Direct DNA base modifications, such as cytosine methylation (mC), are proposed to fundamentally regulate the mammalian genome through altering genome accessibility (Law & Jacobsen 2010). Maladaptive changes in these epigenetic marks are potential drivers of pathogenesis and progression of many diseases (Robertson 2005). In the central nervous system (CNS), epigenetic changes have been associated with a number of age-related diseases, including Alzheimer’s, and cognitive impairment (Penner et al 2010). The hippocampus is a central neural substrate of agerelated dysfunction and disease but previous aging studies have not quantitatively examined mC genome-wide with single base resolution. Albeit in other tissues, provide support for the need to examine alterations in DNA modification with aging (Hahn et al 2017; Petkovich et al 2017; Stubbs et al 2017; Wang et al 2017)
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