Sexually divergent DNA methylation patterns with hippocampal aging

Dustin R. Masser, Niran Hadad, Hunter L. Porter, Colleen A. Mangold, Archana Unnikrishnan, Matthew 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

    14 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

    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., ... 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; 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, M, 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, Dustin R. ; Hadad, Niran ; Porter, Hunter L. ; Mangold, Colleen A. ; Unnikrishnan, Archana ; Ford, Matthew ; 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.
    @article{65333e27a99146cc9d0cc84f4d30cd73,
    title = "Sexually divergent DNA methylation patterns with hippocampal aging",
    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.",
    keywords = "Aging, Divergence, DNA methylation, Epigenetics, Hippocampus, Sex differences",
    author = "Masser, {Dustin R.} and Niran Hadad and Porter, {Hunter L.} and Mangold, {Colleen A.} and Archana Unnikrishnan and Matthew Ford and Giles, {Cory B.} and Constantin Georgescu and Dozmorov, {Mikhail G.} and Wren, {Jonathan D.} and Arlan Richardson and Stanford, {David R.} and Freeman, {Willard M.}",
    year = "2017",
    doi = "10.1111/acel.12681",
    language = "English (US)",
    journal = "Aging Cell",
    issn = "1474-9718",
    publisher = "Wiley-Blackwell",

    }

    TY - JOUR

    T1 - Sexually divergent DNA methylation patterns with hippocampal aging

    AU - Masser, Dustin R.

    AU - Hadad, Niran

    AU - Porter, Hunter L.

    AU - Mangold, Colleen A.

    AU - Unnikrishnan, Archana

    AU - Ford, Matthew

    AU - Giles, Cory B.

    AU - Georgescu, Constantin

    AU - Dozmorov, Mikhail G.

    AU - Wren, Jonathan D.

    AU - Richardson, Arlan

    AU - Stanford, David R.

    AU - Freeman, Willard M.

    PY - 2017

    Y1 - 2017

    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. 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.

    AB - 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.

    KW - Aging

    KW - Divergence

    KW - DNA methylation

    KW - Epigenetics

    KW - Hippocampus

    KW - Sex differences

    UR - http://www.scopus.com/inward/record.url?scp=85030325813&partnerID=8YFLogxK

    UR - http://www.scopus.com/inward/citedby.url?scp=85030325813&partnerID=8YFLogxK

    U2 - 10.1111/acel.12681

    DO - 10.1111/acel.12681

    M3 - Article

    C2 - 28948711

    AN - SCOPUS:85030325813

    JO - Aging Cell

    JF - Aging Cell

    SN - 1474-9718

    ER -