Universal DNA methylation age across mammalian tissues

Aging, often considered a result of random cellular damage, can be accurately estimated using DNA methylation profiles, the foundation of pan-tissue epigenetic clocks. Here, we demonstrate the development of universal pan-mammalian clocks, using 11,754 methylation arrays from our Mammalian Methylation Consortium, which encompass 59 tissue types across 185 mammalian species. These predictive models estimate mammalian tissue age with high accuracy (r > 0.96). Age deviations correlate with human mortality risk, mouse somatotropic axis mutations and caloric restriction. We identified specific cytosines with methylation levels that change with age across numerous species. These sites, highly enriched in polycomb repressive complex 2-binding locations, are near genes implicated in mammalian development, cancer, obesity and longevity. Our findings offer new evidence suggesting that aging is evolutionarily conserved and intertwined with developmental processes across all mammals.Publisher PDFPeer reviewe

Universal DNA methylation age across mammalian tissues.

Aging, often considered a result of random cellular damage, can be accurately estimated using DNA methylation profiles, the foundation of pan-tissue epigenetic clocks. Here, we demonstrate the development of universal pan-mammalian clocks, using 11,754 methylation arrays from our Mammalian Methylation Consortium, which encompass 59 tissue types across 185 mammalian species. These predictive models estimate mammalian tissue age with high accuracy (r > 0.96). Age deviations correlate with human mortality risk, mouse somatotropic axis mutations and caloric restriction. We identified specific cytosines with methylation levels that change with age across numerous species. These sites, highly enriched in polycomb repressive complex 2-binding locations, are near genes implicated in mammalian development, cancer, obesity and longevity. Our findings offer new evidence suggesting that aging is evolutionarily conserved and intertwined with developmental processes across all mammals

Développement de gènes biomarqueurs pour l'évaluation de l’impact des perturbateurs endocrines dans l’espèce non-modèle Gammarus fossarum

National audienceRecently, the urgence in developing relevant tools for the identification and hazard assessment of endocrine disruptors in invertebrate species has been highlighted by the scientific community. However, despite the obvious importance of invertebrates and especially crustaceans in aquatic systems, effects and/or hazard assessment of these compounds remains difficult to establish, and no specific endocrine disruption (ED) biomarkers are available in crustacean species currently used in aquatic ecotoxicology. This can be attributed to the poor knowledge of their endocrine systems, but also to the lack of genomic data for non-model species. Our research teams have conducted recently a “proteogenomic” approach to generate a large transcriptomic and proteomic dataset of the amphipod crustacean Gammarus fossarum, a sentinel species widely used in aquatic ecotoxicology in Europe. Based on this omic ressources and literature research, the aim of this study was to develop and propose specific ED biomarker genes in G. fossarum. We first established an initial candidate list of genes reputed in the literature as essential players of hormonal regulation in crustaceans and insects (hormone receptors, enzymes of the hormone metabolism, regulator genes, hormone-regulated genes). Homologous sequences of crustacean or insect published sequences of these candidates were identified in our transcriptomic G. fossarum database, and a validation step of putative gene annotation was made by sequence similarity research and phylogenetic analyses. With this approach, we identified and validated three potential candidates: the nuclear receptors RxR and E75, and the regulator broad-complex. We then followed a cloning and sequencing protocol to obtain reliable nucleotidic sequence and primers for the posterior expression studies. Their interest as biomarkers was then assessed by studying gene expressions during the male and female reproductive cycles, and after laboratory exposure to model chemical compounds. Perspectives are to develop a methodology for biomarker measurement (sex, size, organ, moulting stage of monitored individuals, duration of exposure) and absolute quantitation methods of proteotypic peptides (immunoassay, and/or mass spectrometry) based on the acquired knowledge of the proteic sequence of these markers in our non-model species

Développement de gènes biomarqueurs de perturbation endocrinienne chez le crustacé non-modèle Gammarus fossarum

International audienceDespite the importance of invertebrates in aquatic systems, we lack specific biomarkers to assess the effects of endocrine disruption (ED) on these animals. This can be attributed to a poor knowledge of their endocrine systems and to the absence of genomic data for non-model species. The development of relevant tools for hazard assessment of ED is currently a challenge for crustacean species used in aquatic ecotoxicology. Our research teams have conducted a “proteogenomic” approach to generate a large transcriptomic and proteomic dataset for the amphipod crustacean Gammarus fossarum, a sentinel species used widely in aquatic ecotoxicology in Europe. Based on these “omic” resources, the aim of this study was to identify, in G. fossarum, some key players involved in the endocrine regulation of crustaceans/amphipods. For this, we first established a list of candidate genes known to play an essential role in hormonal systems of crustaceans and insects: nuclear hormone receptors, other regulatory genes, enzymes of the hormone metabolism and hormone-regulated genes. Using sequence similarity and phylogenetic analyses, we identified similar sequences of three candidate genes in our transcriptomic G. fossarum database: the nuclear receptors RXR and E75, and the regulator broad-complex. The three genes were cloned in order to obtain reliable nucleotide sequences and primers for the subsequent expression studies. Their validation as biomarkers was then performed by studying gene expression during the male and female reproductive cycles, and after laboratory exposure to model ED chemical compounds

Activation of p38, p21, and NRF-2 mediates decreased proliferation of human dental pulp stem cells cultured under 21% O₂

High rates of stem cell proliferation are important in regenerative medicine and in stem cell banking for clinical use. Ambient oxygen tensions (21% O2) are normally used for in vitro culture, but physiological levels in vivo range between 3% and 6% O2. We compared proliferation of human dental pulp stem cells (hDPSCs) cultured under 21% versus 3% O2. The rate of hDPSC proliferation is significantly lower at 21% O2 compared to physiological oxygen levels due to enhanced oxidative stress. Under 21% O2, increased p38 phosphorylation led to activation of p21. Increased generation of reactive oxygen species and p21 led to activation of the NRF-2 signaling pathway. The upregulation of NRF-2 antioxidant defense genes under 21% O2 may interact with cell-cycle-related proteins involved in regulating cell proliferation. Activation of p38/p21/NRF-2 in hDPSCs cultured under ambient oxygen tension inhibits stem cell proliferation and upregulates NRF-2 antioxidant defenses