Sexually divergent DNA methylation patterns with hippocampal aging |
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| Authors: | Hunter L Porter Colleen A Mangold Archana Unnikrishnan Matthew M Ford Cory B Giles Constantin Georgescu Mikhail G Dozmorov Jonathan D Wren Arlan Richardson David R Stanford Willard M Freeman |
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| Institution: | 1. Reynolds Oklahoma Center on Aging, Oklahoma, OK, USA;2. Oklahoma Nathan Shock Center for Aging, Oklahoma, OK, USA;3. Oklahoma Center for Neuroscience, University of Oklahoma Health Sciences Center, Oklahoma, OK, USA;4. Department of Biochemistry and Molecular Biology, Pennsylvania State University, University Park, PA, USA;5. Department of Geriatric Medicine, University of Oklahoma Health Sciences Center, Oklahoma, OK, USA;6. Division of Neuroscience, Oregon National Primate Research Center, Beaverton, OR, USA;7. Arthritis & Clinical Immunology Program, Oklahoma Medical Research Foundation, Oklahoma, OK, USA;8. Department of Biostatistics, Virginia Commonwealth University School of Medicine, Richmond, VA, USA;9. Department of Biochemistry and Molecular Biology, University of Oklahoma Health Sciences Center, Oklahoma, OK, USA;10. Department of Physiology, University of Oklahoma Health Sciences Center, Oklahoma, OK, USA;11. Oklahoma City VA Medical Center, Oklahoma, OK, USA |
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| Abstract: | 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. |
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| Keywords: | aging divergence DNA methylation epigenetics hippocampus sex differences |
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