Sexually divergent DNA methylation patterns with hippocampal aging

Dustin R. Masser, Niran Hadad, 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

Research output: Contribution to journalArticle

13 Citations (Scopus)

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.

Original languageEnglish (US)
JournalAging Cell
DOIs
StateAccepted/In press - 2017
Externally publishedYes

Fingerprint

DNA Methylation
Methylation
Genome
Epigenomics
Sex Characteristics
Hippocampus
Sex Factors
Intergenic DNA
Cytosine
Islands
Neurodegenerative Diseases
Animal Models
Mortality

Keywords

  • Aging
  • Divergence
  • DNA methylation
  • Epigenetics
  • Hippocampus
  • Sex differences

ASJC Scopus subject areas

  • Aging
  • Cell Biology

Cite this

Masser, D. R., Hadad, N., Porter, H. L., Mangold, C. A., Unnikrishnan, A., Ford, M. M., ... Freeman, W. M. (Accepted/In press). Sexually divergent DNA methylation patterns with hippocampal aging. Aging Cell. https://doi.org/10.1111/acel.12681

Sexually divergent DNA methylation patterns with hippocampal aging. / Masser, Dustin R.; Hadad, Niran; Porter, Hunter L.; Mangold, Colleen A.; Unnikrishnan, Archana; Ford, Matthew M.; Giles, Cory B.; Georgescu, Constantin; Dozmorov, Mikhail G.; Wren, Jonathan D.; Richardson, Arlan; Stanford, David R.; Freeman, Willard M.

In: Aging Cell, 2017.

Research output: Contribution to journalArticle

Masser, DR, Hadad, N, Porter, HL, Mangold, CA, Unnikrishnan, A, Ford, MM, Giles, CB, Georgescu, C, Dozmorov, MG, Wren, JD, Richardson, A, Stanford, DR & Freeman, WM 2017, 'Sexually divergent DNA methylation patterns with hippocampal aging', Aging Cell. https://doi.org/10.1111/acel.12681
Masser DR, Hadad N, Porter HL, Mangold CA, Unnikrishnan A, Ford MM et al. Sexually divergent DNA methylation patterns with hippocampal aging. Aging Cell. 2017. https://doi.org/10.1111/acel.12681
Masser, Dustin R. ; Hadad, Niran ; Porter, Hunter L. ; Mangold, Colleen A. ; Unnikrishnan, Archana ; Ford, Matthew M. ; Giles, Cory B. ; Georgescu, Constantin ; Dozmorov, Mikhail G. ; Wren, Jonathan D. ; Richardson, Arlan ; Stanford, David R. ; Freeman, Willard M. / Sexually divergent DNA methylation patterns with hippocampal aging. In: Aging Cell. 2017.
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