TY - JOUR T1 - Sexually divergent DNA methylation programs with hippocampal aging JF - bioRxiv DO - 10.1101/161752 SP - 161752 AU - Dustin R. Masser AU - Niran Hadad AU - Hunter Porter AU - Colleen A. Mangold AU - Archana Unnikrishnan AU - Matthew M. Ford AU - Cory B. Giles AU - Constantin Georgescu AU - Mikhail G. Dozmorov AU - Jonathan D. Wren AU - Arlan Richardson AU - David R. Stanford AU - Willard M. Freeman Y1 - 2017/01/01 UR - http://biorxiv.org/content/early/2017/07/10/161752.abstract N2 - 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. Life-long 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 were 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. ER -