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  • 1
    Online Resource
    Online Resource
    DNA methylation networks underlying mammalian traits
    American Association for the Advancement of Science (AAAS) ; 2023
    In:  Science Vol. 381, No. 6658 ( 2023-08-11)
    Details
    In: Science, American Association for the Advancement of Science (AAAS), Vol. 381, No. 6658 ( 2023-08-11)
    Abstract: Comparative epigenomics is an emerging field that combines epigenetic signatures with phylogenetic relationships to elucidate species characteristics such as maximum life span. For this study, we generated cytosine DNA methylation (DNAm) profiles ( n = 15,456) from 348 mammalian species using a methylation array platform that targets highly conserved cytosines. RATIONALE Nature has evolved mammalian species of greatly differing life spans. To resolve the relationship of DNAm with maximum life span and phylogeny, we performed a large-scale cross-species unsupervised analysis. Comparative studies in many species enables the identification of epigenetic correlates of maximum life span and other traits. RESULTS We first tested whether DNAm levels in highly conserved cytosines captured phylogenetic relationships among species. We constructed phyloepigenetic trees that paralleled the traditional phylogeny. To avoid potential confounding by different tissue types, we generated tissue-specific phyloepigenetic trees. The high phyloepigenetic-phylogenetic congruence is due to differences in methylation levels and is not confounded by sequence conservation. We then interrogated the extent to which DNA methylation associates with specific biological traits. We used an unsupervised weighted correlation network analysis (WGCNA) to identify clusters of highly correlated CpGs (comethylation modules). WGCNA identified 55 distinct comethylation modules, of which 30 were significantly associated with traits including maximum life span, adult weight, age, sex, human mortality risk, or perturbations that modulate murine life span. Both the epigenome-wide association analysis (EWAS) and eigengene-based analysis identified methylation signatures of maximum life span, and most of these were independent of aging, presumably set at birth, and could be stable predictors of life span at any point in life. Several CpGs that are more highly methylated in long-lived species are located near HOXL subclass homeoboxes and other genes that play a role in morphogenesis and development. Some of these life span–related CpGs are located next to genes that are also implicated in our analysis of upstream regulators (e.g., ASCL1 and SMAD6 ). CpGs with methylation levels that are inversely related to life span are enriched in transcriptional start site (TSS1) and promoter flanking (PromF4, PromF5) associated chromatin states. Genes located in chromatin state TSS1 are constitutively active and enriched for nucleic acid metabolic processes. This suggests that long-living species evolved mechanisms that maintain low methylation levels in these chromatin states that would favor higher expression levels of genes essential for an organism’s survival. The upstream regulator analysis of the EWAS of life span identified the pluripotency transcription factors OCT4 , SOX2 , and NANOG. Other factors, such as POLII , CTCF , RAD21 , YY1 , and TAF1 , showed the strongest enrichment for negatively life span–related CpGs. CONCLUSION The phyloepigenetic trees indicate that divergence of DNA methylation profiles closely parallels that of genetics through evolution. Our results demonstrate that DNA methylation is subjected to evolutionary pressures and selection. The publicly available data from our Mammalian Methylation Consortium are a rich source of information for different fields such as evolutionary biology, developmental biology, and aging. DNAm network relates to mammalian phylogeny and traits. ( A ) Phyloepigenetic tree from the DNAm data generated from blood samples. ( B ) Unsupervised WGCNA networks identified 55 comethylation modules. ( C ) EWAS of log-transformed maximum life span. Each dot corresponds to the methylation levels of a highly conserved CpG. Shown is the log (base 10)–transformed P value ( y axis) versus the human genome coordinate Hg19 ( x axis). ( D ) Comethylation module correlated with maximum life span of mammals. Eigengene (first principal component of scaled CpGs in the midnightblue module) versus log (base e) transformed maximum life span. Each dot corresponds to a different species.
    Type of Medium: Online Resource
    ISSN: 0036-8075 , 1095-9203
    URL: Article
    DOI: 10.1126/science.abq5693
    RVK:
    TA 1000
    RVK:
    WA 15000
    Language: English
    Publisher: American Association for the Advancement of Science (AAAS)
    Publication Date: 2023
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    detail.hit.zdb_id: 2066996-3
    SSG: 11
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  • 2
    Online Resource
    Online Resource
    Pan-primate studies of age and sex
    Springer Science and Business Media LLC ; 2023
    In:  GeroScience Vol. 45, No. 6 ( 2023-07-26), p. 3187-3209
    Details
    In: GeroScience, Springer Science and Business Media LLC, Vol. 45, No. 6 ( 2023-07-26), p. 3187-3209
    Abstract: Age and sex have a profound effect on cytosine methylation levels in humans and many other species. Here we analyzed DNA methylation profiles of 2400 tissues derived from 37 primate species including 11 haplorhine species (baboons, marmosets, vervets, rhesus macaque, chimpanzees, gorillas, orangutan, humans) and 26 strepsirrhine species (suborders Lemuriformes and Lorisiformes). From these we present here, pan-primate epigenetic clocks which are highly accurate for all primates including humans (age correlation R = 0.98). We also carried out in-depth analysis of baboon DNA methylation profiles and generated five epigenetic clocks for baboons (Olive-yellow baboon hybrid), one of which, the pan-tissue epigenetic clock, was trained on seven tissue types (fetal cerebral cortex, adult cerebral cortex, cerebellum, adipose, heart, liver, and skeletal muscle) with ages ranging from late fetal life to 22.8 years of age. Using the primate data, we characterize the effect of age and sex on individual cytosines in highly conserved regions. We identify 11 sex-related CpGs on autosomes near genes ( POU3F2, CDYL, MYCL, FBXL4, ZC3H10, ZXDC, RRAS, FAM217A, RBM39, GRIA2, UHRF2 ). Low overlap can be observed between age- and sex-related CpGs. Overall, this study advances our understanding of conserved age- and sex-related epigenetic changes in primates, and provides biomarkers of aging for all primates.
    Type of Medium: Online Resource
    ISSN: 2509-2723
    URL: Article
    DOI: 10.1007/s11357-023-00878-3
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2023
    detail.hit.zdb_id: 2886418-9
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  • 3
    Online Resource
    Online Resource
    Epigenetic predictors of species maximum life span and other life-history traits in mammals
    American Association for the Advancement of Science (AAAS) ; 2024
    In:  Science Advances Vol. 10, No. 23 ( 2024-06-07)
    Details
    In: Science Advances, American Association for the Advancement of Science (AAAS), Vol. 10, No. 23 ( 2024-06-07)
    Abstract: DNA methylation can estimate maximum mammal life span, but the predictor does not correlate with individual mortality risk.
    Type of Medium: Online Resource
    ISSN: 2375-2548
    URL: Article
    DOI: 10.1126/sciadv.adm7273
    Language: English
    Publisher: American Association for the Advancement of Science (AAAS)
    Publication Date: 2024
    detail.hit.zdb_id: 2810933-8
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  • 4
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    Online Resource
    Multi-species and multi-tissue methylation clocks for age estimation in toothed whales and dolphins
    Springer Science and Business Media LLC ; 2021
    In:  Communications Biology Vol. 4, No. 1 ( 2021-05-31)
    Details
    In: Communications Biology, Springer Science and Business Media LLC, Vol. 4, No. 1 ( 2021-05-31)
    Abstract: The development of a precise blood or skin tissue DNA Epigenetic Aging Clock for Odontocete (OEAC) would solve current age estimation inaccuracies for wild odontocetes. Therefore, we determined genome-wide DNA methylation profiles using a custom array (HorvathMammalMethyl40) across skin and blood samples (n = 446) from known age animals representing nine odontocete species within 4 phylogenetic families to identify age associated CG dinucleotides (CpGs). The top CpGs were used to create a cross-validated OEAC clock which was highly correlated for individuals (r = 0.94) and for unique species (median r = 0.93). Finally, we applied the OEAC for estimating the age and sex of 22 wild Norwegian killer whales. DNA methylation patterns of age associated CpGs are highly conserved across odontocetes. These similarities allowed us to develop an odontocete epigenetic aging clock (OEAC) which can be used for species conservation efforts by provide a mechanism for estimating the age of free ranging odontocetes from either blood or skin samples.
    Type of Medium: Online Resource
    ISSN: 2399-3642
    URL: Article
    DOI: 10.1038/s42003-021-02179-x
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2021
    detail.hit.zdb_id: 2919698-X
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