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Epigenetic clocks reveal a rejuvenation event during embryogenesis followed by aging

Kerepesi, Csaba, Zhang, Bohan, Lee, Sang-Goo, Trapp, Alexandre, Gladyshev, Vadim N.·2021·Science Advances
DOI 10.1126/sciadv.abg6082PMC PMC8232908

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Abstract

Epigenetic clocks reveal a rejuvenation event during embryogenesis followed by aging.

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Fig. 1 A rejuvenation event during early embryogenesis revealed by aging clocks. (A) Overview of the model, which posits that germline cells age during development and adulthood and are rejuvenated in the offspring after conception. The model also suggests that there is a time point corresponding to the lowest biological age (ground zero). (B) Multi-tissue and blood rDNA clocks applied to five datasets spanning the first 8 days of mouse embryogenesis (Table 1, datasets 1 to 5). We rescaled epigenetic age of each dataset to the interval [0,1] for comparison (“relative rDNA age”). 0 represents the lowest epigenetic age, and 1 represents the highest epigenetic age of each dataset. Blue lines indicate the mean of each group; P values of two-sided t test comparing the means of the two groups (before and after E6) are displayed. (C) Application of four genome-wide epigenetic aging clocks to two available mouse RRBS datasets. (D) Epigenetic age of human ESCs and iPSCs as a function of passage number. The Horvath human multi-tissue clock was applied.
Fig. 1 A rejuvenation event during early embryogenesis revealed by aging clocks. (A) Overview of the model, which posits that germline cells age during development and adulthood and are rejuvenated in the offspring after conception. The model also suggests that there is a time point corresponding to the lowest biological age (ground zero). (B) Multi-tissue and blood rDNA clocks applied to five datasets spanning the first 8 days of mouse embryogenesis (Table 1, datasets 1 to 5). We rescaled epigenetic age of each dataset to the interval [0,1] for comparison (“relative rDNA age”). 0 represents the lowest epigenetic age, and 1 represents the highest epigenetic age of each dataset. Blue lines indicate the mean of each group; P values of two-sided t test comparing the means of the two groups (before and after E6) are displayed. (C) Application of four genome-wide epigenetic aging clocks to two available mouse RRBS datasets. (D) Epigenetic age of human ESCs and iPSCs as a function of passage number. The Horvath human multi-tissue clock was applied.CC BY-NC · PubMed Central
Fig. 2 Organismal aging begins in mid-embryonic development in mice and humans. (A) Epigenetic age (multi-tissue and blood rDNA clocks) analysis of the dataset that contains both early and late mouse embryo samples (E13.5 samples are based on primordial germline cells). (B) Application of genome-wide epigenetic clocks to later stages of mouse embryogenesis (r, Pearson correlation coefficient; P, P value of the correlation). (C) The same data as above but separated by tissue. An increasing trend is observed for almost all tissues, with few nonsignificant exceptions. (D) Epigenetic age dynamics of four independent prenatal human 450K methylation array datasets based on the Horvath human multi-tissue clock. (E) The same data as above but separated by tissue (five significant increases, nine nonsignificant increases, four nonsignificant decreases, and zero significant decreases).
Fig. 2 Organismal aging begins in mid-embryonic development in mice and humans. (A) Epigenetic age (multi-tissue and blood rDNA clocks) analysis of the dataset that contains both early and late mouse embryo samples (E13.5 samples are based on primordial germline cells). (B) Application of genome-wide epigenetic clocks to later stages of mouse embryogenesis (r, Pearson correlation coefficient; P, P value of the correlation). (C) The same data as above but separated by tissue. An increasing trend is observed for almost all tissues, with few nonsignificant exceptions. (D) Epigenetic age dynamics of four independent prenatal human 450K methylation array datasets based on the Horvath human multi-tissue clock. (E) The same data as above but separated by tissue (five significant increases, nine nonsignificant increases, four nonsignificant decreases, and zero significant decreases).CC BY-NC · PubMed Central
Fig. 3 Epigenetic age of mouse ESCs during early passaging under different culture conditions. (A) Epigenetic age (by rDNA clocks) of mouse ESCs after outgrowth (passage 0) and passage 5 under three different culture conditions (2i, both self-renewal supporting inhibitors used; PD, only one inhibitor; mES, no inhibitor). (B) Application of genome-wide mouse epigenetic clocks to the same data. (C) Principal components analysis (PCA) of RRBS methylation profiles of embryo (circles) and ESC (crosses) sample groups after passage 0 (left) and passage 5 (right). Convex hull around the ESC samples in the same group (if n > 2) is displayed to help distinguish ESC samples from embryo samples.
Fig. 3 Epigenetic age of mouse ESCs during early passaging under different culture conditions. (A) Epigenetic age (by rDNA clocks) of mouse ESCs after outgrowth (passage 0) and passage 5 under three different culture conditions (2i, both self-renewal supporting inhibitors used; PD, only one inhibitor; mES, no inhibitor). (B) Application of genome-wide mouse epigenetic clocks to the same data. (C) Principal components analysis (PCA) of RRBS methylation profiles of embryo (circles) and ESC (crosses) sample groups after passage 0 (left) and passage 5 (right). Convex hull around the ESC samples in the same group (if n > 2) is displayed to help distinguish ESC samples from embryo samples.CC BY-NC · PubMed Central
Fig. 4 Localization of the epigenetic age minimum (ground zero) during mouse embryonic development. (A) We concatenated results for the entire period of embryogenesis by using the genome-wide mouse epigenetic clocks indicated. (B) We concatenated results for the entire period of embryogenesis by using the indicated mouse rDNA epigenetic clocks. (C) Application of genome-wide mouse epigenetic clocks to dataset 20 that contains mid-embryonic stages from E3.5 to E11.5. (D) Application of rDNA mouse epigenetic clocks to dataset 20.
Fig. 4 Localization of the epigenetic age minimum (ground zero) during mouse embryonic development. (A) We concatenated results for the entire period of embryogenesis by using the genome-wide mouse epigenetic clocks indicated. (B) We concatenated results for the entire period of embryogenesis by using the indicated mouse rDNA epigenetic clocks. (C) Application of genome-wide mouse epigenetic clocks to dataset 20 that contains mid-embryonic stages from E3.5 to E11.5. (D) Application of rDNA mouse epigenetic clocks to dataset 20.CC BY-NC · PubMed Central
Fig. 5 Role of TET enzymes in the rejuvenation event. (A) Application of rDNAm clocks to TET triple KO (TET KO) and wild-type (WT) E6.5 epiblast samples (dataset 17). (B) Application of our recently developed single-cell clock [scAge; (49)] to TET KO and WT ESCs at days 2 and 5 of differentiation (dataset 18). Specific lineages and stages (Mapped lineage and Mapped E-day) were assigned by mapping the RNA expression profiles of the in vitro cells to an in vivo gastrulation atlas. Two-sided t tests were calculated (ns, P > 0.05; *, 1 × 10−2 < P ≤ 5 × 10−2; **, 1 × 10−3 < P ≤ 1 × 10−2; ***, 1 × 10−4 < P ≤ 1 × 10−3; ****P ≤ 1 × 10−4).
Fig. 5 Role of TET enzymes in the rejuvenation event. (A) Application of rDNAm clocks to TET triple KO (TET KO) and wild-type (WT) E6.5 epiblast samples (dataset 17). (B) Application of our recently developed single-cell clock [scAge; (49)] to TET KO and WT ESCs at days 2 and 5 of differentiation (dataset 18). Specific lineages and stages (Mapped lineage and Mapped E-day) were assigned by mapping the RNA expression profiles of the in vitro cells to an in vivo gastrulation atlas. Two-sided t tests were calculated (ns, P > 0.05; *, 1 × 10−2 < P ≤ 5 × 10−2; **, 1 × 10−3 < P ≤ 1 × 10−2; ***, 1 × 10−4 < P ≤ 1 × 10−3; ****P ≤ 1 × 10−4).CC BY-NC · PubMed Central
Fig. 6 Role of DNMTs in the rejuvenation event. (A) We applied rDNA clocks to single KO of DNMT1 (Dnmt1−/−), double KO of DNMT3A and DNMT3B (DKO), wild type (WT), and heterozygous control (3a−/+ and 3a−/+ 3b−/+) embryos at E8.5 (dataset 19). (B) Application of four genome-wide epigenetic aging clocks to the same dataset. Two-sided t tests were calculated (ns, P > 0.05; *, 1 × 10−2 < P ≤ 5 × 10−2; **, 1 × 10−3 < P ≤ 1 × 10−2; ***, 1 × 10−4 < P ≤ 1 × 10−3; ****P ≤ 1 × 10−4).
Fig. 6 Role of DNMTs in the rejuvenation event. (A) We applied rDNA clocks to single KO of DNMT1 (Dnmt1−/−), double KO of DNMT3A and DNMT3B (DKO), wild type (WT), and heterozygous control (3a−/+ and 3a−/+ 3b−/+) embryos at E8.5 (dataset 19). (B) Application of four genome-wide epigenetic aging clocks to the same dataset. Two-sided t tests were calculated (ns, P > 0.05; *, 1 × 10−2 < P ≤ 5 × 10−2; **, 1 × 10−3 < P ≤ 1 × 10−2; ***, 1 × 10−4 < P ≤ 1 × 10−3; ****P ≤ 1 × 10−4).CC BY-NC · PubMed Central

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Metadata

Authors
Kerepesi, C., Zhang, B., Lee, S.-G., Trapp, A., & Gladyshev, V. N.
Affiliations
Division of Genetics, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA 02115, USA.
ORCID
Venue
Science Advances
Publisher
American Association for the Advancement of Science (AAAS)
Published
2021-06-25
Volume
7
Issue
26
ISSN
2375-2548
DOI
10.1126/sciadv.abg6082
PMC
PMC8232908
Cited by
130
References
18
Language
en
Licence
creativecommons.org/licenses/by-nc/4.0/ (vor)
Funders
  • National Institutes of Health (AG064223)
  • National Institute on Aging (AG067782, AG065403)

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