Abstract
Gametes are highly specialized cells that can give rise to the next generation through their ability to generate a totipotent zygote. In mice, germ cells are first specified in the developing embryo around embryonic day (E) 6.25 as primordial germ cells (PGCs)1. Following subsequent migration into the developing gonad, PGCs undergo a wave of extensive epigenetic reprogramming around E10.5–E11.52,3,4,5,6,7,8,9,10,11, including genome-wide loss of 5-methylcytosine2,3,4,5,7,8,9,10,11. The underlying molecular mechanisms of this process have remained unclear, leading to our inability to recapitulate this step of germline development in vitro12,13,14. Here we show, using an integrative approach, that this complex reprogramming process involves coordinated interplay among promoter sequence characteristics, DNA (de)methylation, the polycomb (PRC1) complex and both DNA demethylation-dependent and -independent functions of TET1 to enable the activation of a critical set of germline reprogramming-responsive genes involved in gamete generation and meiosis. Our results also reveal an unexpected role for TET1 in maintaining but not driving DNA demethylation in gonadal PGCs. Collectively, our work uncovers a fundamental biological role for gonadal germline reprogramming and identifies the epigenetic principles of the PGC-to-gonocyte transition that will help to guide attempts to recapitulate complete gametogenesis in vitro.
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14 March 2018
The received date was corrected in the HTML from 21 July 2015 to 21 July 2017.
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Acknowledgements
We thank J. Elliot and T. Adejumo for help with fluorescence activated cell sorting, L. Game for help with next-generation sequencing, F. Krueger for providing consensus repetitive element sequences, M. Woodberry, A. Cameron, and J. Glegola for mouse husbandry, T. Carell for a gift of isotopically labelled deoxynucleoside standards and the members of the Hajkova laboratory for discussions and revisions of the manuscript. Work in the Hajkova laboratory is supported by MRC funding (MC_US_A652_5PY70), the FP7 EpiGeneSys network and an ERC grant (ERC-CoG-648879–dynamicmodifications) to P.H. The laboratory of Y.Z. and S.P. is supported by grant 1R44GM096723-01A1. P.H. is a member of the EMBO Young Investigator Programme. P.W.S.H. is a recipient of an MRC PhD Studentship and MRC-targeted Doctoral Prize Fellowship from Imperial College London.
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P.H. and P.W.S.H. conceived the study; P.W.S.H. performed the experiments and analysed the data; H.G.L. carried out mouse ES cell experiments with the help of M.B. and M.R.-T.; C.E.R. generated Tet1−/− DNMT TKO mouse ES cell line with the help of H.B.; R.A. carried out LC–MS/MS experiments and analysed the data with the help of S.L.; J.T. made Aba–seq libraries with support from Y.Z.; computational analysis was carried out by P.W.S.H. with the help of Z.S., G.D., V.H., and B.L.; R.V. performed experiments; P.W.S.H. and P.H. wrote the manuscript with assistance from S.P. and B.L.
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Extended data figures and tables
Extended Data Figure 1 Characterization of WGBS datasets and validation of Aba–seq method.
a, Distribution of WGBS coverage for each symmetric CpG. For box plots, the upper and lower hinges correspond to the first and third quartiles, the centre line corresponds to the median, and the maxima and minima correspond to the highest and lowest value within 1.5 × the inter-quartile range, respectively. b, Overview of the Aba–seq method15. c–e, Density heat map showing correlation between levels of 5hmC at all 2-kb windows (minimum of four symmetric CpGs) in E14 mouse ES cells as computed by TAB–seq35 (x-axis) and Aba–seq15 (y-axis) (c); TAB–seq35 (x-axis) and hMeDIP36 (y-axis) (d) or Aba–seq15 (x-axis) and hMeDIP36 (y-axis) (e). For c–e, the Pearson correlation coefficient (ρ) is shown. Specific details for all Extended Data Figures regarding sample sizes and how samples were collected can be found in the ‘Statistics and reproducibility’ section.
Extended Data Figure 2 Further analysis of the levels of 5hmC in E10.5 PGCs.
a, Density heat map showing the levels of 5hmC per 2-kb window (with minimum four CpGs) for E10.5 PGCs (y-axis) and E14 mouse ES cells15 (x-axis). The Pearson correlation coefficient (ρ) is shown. b, Levels of 5hmC (ascertained using Aba–seq) at various regulatory elements in E10.5 PGCs (left) or E14 mouse ES cells15 (right). P values are based on ANOVA and Dunnett’s post hoc test. For box plots, the upper and lower hinges correspond to the first and third quartiles, the centre line corresponds to the median, and the maxima and minima correspond to the highest and lowest value within 1.5 × the inter-quartile range, respectively. c, Metagene plot showing the levels of 5hmC (determined using Aba–seq) (top) and the combined levels of 5mC and 5hmC (determined using WGBS) (bottom) in E10.5 PGCs across genes expressed at different levels in E10.5 PGCs. d, e, Metagene plot showing the levels of 5hmC (determined using Aba–seq) (top) and the combined levels of 5mC and 5hmC (determined using WGBS) (bottom) in E10.5 PGCs across either putative active enhancers (d) or CpG islands (e). f, Bar chart showing the levels of 5hmC at ICRs in E14 mouse ES cells as determined by TAB–seq35 (%; light green) or Aba–seq15 (read counts; dark green), or in E10.5 PGCs as determined by Aba–seq (read counts; orange).
Extended Data Figure 3 Further analysis of 5mC and 5hmC dynamics in PGCs.
a, Combined levels of 5mC and 5hmC as determined by WGBS (left) or levels of 5hmC as determined by Aba–seq (right) at various features within the uniquely mapped part of the genome in PGCs between E10.5 and E12.5. For box plots, the upper and lower hinges correspond to the first and third quartiles, the centre line corresponds to the median, and the maxima and minima correspond to the highest or lowest value within 1.5 × the inter-quartile range, respectively. b, The combined levels of 5mC and 5hmC (determined by WGBS) (left) or levels of 5hmC (determined by Aba–seq) (right) at various consensus repetitive elements in PGCs between E10.5 and E12.5. Asterisks indicate mean values.
Extended Data Figure 4 5hmC is targeted to newly hypomethylated regions following DNA demethylation in mouse gonadal PGCs.
See also Extended Data Fig. 5. a, Density heat map showing Pearson correlation (ρ) between levels of 5hmC for E10.5 PGC biological replicates (left), for E10.5 and E11.5 PGCs (middle), and for E10.5 and E12.5 PGCs (right). b, Mean Z-scores depicting levels of 5hmC (determined by Aba–seq) (orange) and combined levels of 5mC and 5hmC (determined by WGBS) (grey) for each stage normalized to the average level of either 5hmC or combined 5mC and 5hmC across stages. Standard error of the mean is shown but it is too small to see. c–f, Density heat maps showing the correlation between the total (c, d) or relative (e, f) levels of 5hmC in E10.5 (c, e) or E11.5 (d, f) PGCs and the change in the combined levels of 5mC and 5hmC in PGCs between these two stages for all 2-kb windows with a minimum 20% combined 5mC and 5hmC in E10.5 PGCs. g, Density heat map showing the correlation between the relative levels of 5hmC in E11.5 PGCs and the combined level of 5mC and 5hmC in E11.5 PGCs for all 2-kb windows with a minimum 20% combined 5mC and 5hmC in E10.5 PGCs. h, Combined levels of 5mC and 5hmC in E10.5 and E11.5 PGCs for 2-kb windows with a minimum 20% combined 5mC and 5hmC in E10.5 PGCs that are either 1) enriched for total levels of 5hmC at either E10.5 or E11.5 (green, upper-tail adjusted Poisson P < 0.05), or 2) depleted of total 5hmC at both E10.5 and E11.5 (red, lower-tail adjusted Poisson P < 0.05). i, Density plot showing the decrease in combined levels of 5mC and 5hmC in PGCs between E10.5 and E11.5 for 2-kb windows with a minimum 20% total DNA modification in E10.5 PGCs that are either 1) enriched for total levels of 5hmC at either E10.5 or E11.5 (green, upper-tail adjusted Poisson P < 0.05), or 2) depleted of total 5hmC at both E10.5 and E11.5 (red, lower-tail adjusted Poisson P < 0.05). For all box plots, the upper and lower hinges correspond to the first and third quartiles, the centre line corresponds to the median, and the maxima and minima correspond to the highest or lowest value within 1.5 × the inter-quartile range, respectively. P values are based on a two-sided Wilcoxon test. Note that for density heat maps, the Spearman correlation (ρS) is shown and the red line represents the smoothed mean as determined by a generalized additive model.
Extended Data Figure 5 Suggested models implicating 5mC oxidation in DNA demethylation of gonadal PGCs.
a, A model of oxidation followed by passive dilution predicts a positive correlation between the extent to which the combined levels of 5mC and 5hmC decrease between two stages (as determined by WGBS) and the total level of 5hmC at both the stage immediately preceding and following the decrease. b, A model implicating 5mC oxidation in triggering DNA demethylation via an active mechanism predicts a positive correlation between the extent to which the combined levels of 5mC and 5hmC decrease between two stages (as determined by WGBS) and the relative levels of 5hmC in the stage immediately preceding this decrease, as further oxidation of 5hmC to 5-formylcytosine (5fC) is the rate-limiting step in the full oxidation of 5mC to 5-carboxylcytosine (5caC) (ref. 39). c, A model implicating oxidation of 5mC in safeguarding DNA hypomethylation following the major wave of DNA demethylation predicts that regions where the majority of DNA methylation has been lost between two stages (that is, those that are newly hypomethylated) will have high relative levels of 5hmC in the stage immediately after the major wave of DNA demethylation in order to remove residual methylation and/or aberrant de novo methylation. Thus, a limited correlation between the extent to which the combined levels of 5mC and 5hmC decrease between two stages (as determined by WGBS) and the relative levels of 5hmC in the stage immediately following this decrease may also be seen.
Extended Data Figure 6 Expression of TET1, TET2 and TET3 and locus-specific DNA methylation in Tet1−/− PGCs during epigenetic reprogramming.
a, Expression of Tet1 total transcript (left) or Tet1 exon 4 (right) in E12.5 Tet1−/− and wild-type PGCs. Adjusted P values (left) computed by DESeq2 and P values (right) computed by Student’s t-test. Asterisks indicate mean values. b, Representative immunostaining against the N terminus of TET1 protein in E12.5 wild-type and Tet1−/− PGCs. Scale bars represent 10 μm. c, Expression of Tet2 and Tet3 in E12.5 Tet1−/− and wild-type PGCs. Adjusted P values computed by DESeq2. Asterisks indicate mean values. d, e, Mean combined levels of 5hmC and 5mC (determined using RRBS) in female (d) or male (e) E12.5 and E14.5 Tet1−/− and wild-type PGCs for ICRs and germline gene promoters labelled as hypermethylated in E14.5 Tet1−/− PGCs. The mean DNA modification level and P values were computed using RnBeads software (see Methods). f, g, Locus-specific bisulfite sequencing of the Dazl promoter (left), the Peg3 ICR (middle) and the IG-DMR ICR (right) in E12.5 (f) and E13.5 (g) female Tet1−/− and wild-type PGCs.
Extended Data Figure 7 Promoter DNA methylation clustering analysis during germline reprogramming.
a, The combined levels of 5mC and 5hmC at promoters (ascertained using WGBS) (right), levels of 5hmC at promoters (ascertained by Aba–seq) (centre), or gene expression levels (RNA-seq data) (right) in consecutive stages of PGC development for all genes grouped by k-means clustering of the combined 5mC and 5hmC dynamics at their promoter regions. b, c, Box plots depicting the combined levels of 5mC and 5hmC at promoters (ascertained using WGBS) (left), levels of 5hmC at promoters (ascertained using Aba–seq) (centre), or gene expression levels (RNA-seq data) (right) in consecutive stages of PGC development for three clusters of genes with either low CpG promoters (b) or intermediate CpG promoters (c) grouped by k-means clustering of the combined 5mC and 5hmC dynamics at their promoter regions. For all box plots, the upper and lower hinges correspond to the first and third quartiles, the centre line corresponds to the median, and the maxima and minima correspond to the highest and lowest values within 1.5 × the inter-quartile range, respectively.
Extended Data Figure 8 DNA modification and expression dynamics in wild-type and Tet1−/− PGCs at retrotransposons normally activated concurrently with epigenetic reprogramming.
a, b, Combined 5mC and 5hmC dynamics in wild-type PGCs (%; WGBS; far left); relative 5hmC dynamics (Aba–seq read counts normalized to E10.5) in wild-type PGCs (centre left); the expression dynamics in either wild-type or Tet1−/− PGCs (transcripts per million (TPM); RNA-seq data; centre right); and the combined dynamics of 5mC and 5hmC in wild-type and Tet1−/− PGCs (%; RRBS; far right) for representative repetitive elements (IAPA_MM, IAPEZI and L1mdTf_II) that are significantly upregulated (adjusted P < 0.05; Sleuth) in a sex-independent manner (a), a male-specific manner (b, blue outline) or a female-specific manner (b, pink outline) between E10.5 and E14.5 in wild-type PGCs. Mean values are shown in all cases. Adjusted P values for differential repeat expression analysis between E14.5 wild-type and Tet1−/− PGCs are based on Sleuth software.
Extended Data Figure 9 Characterization of GRR gene regulation by TET1 and 5mC in PGCs and mouse ES cells.
a, CpG density at GRR gene promoters and other relevant promoters; P values are based on a two-sided Wilcoxon test. b, Mean 5hmC dynamics at GRR gene promoters and non-activated methylated and demethylated HCPs in PGCs; P values are based on a two-sided paired Wilcoxon test. c, log2(fold change) between Tet1−/− and wild-type E14.5 male (blue) or female (pink) PGCs for GRR genes and other relevant gene sets. FWER-adjusted P values are based on GSEA software (see Methods). d, log2(fold change) between Dnmt1CKO (ref. 24) and wild-type mouse PGCs (green), or between E14.5 female (pink) or male (blue) wild-type PGCs and E10.5 wild-type PGCs, for GRR genes and other relevant gene sets. FWER-adjusted P values are based on GSEA software (see Methods). e, Correlation between the difference in the combined levels of 5mC and 5hmC (%, ascertained by RRBS) (x-axis: Tet1−/− − wild type (WT)) at GRR promoters and the change in GRR gene expression (y-axis; log2(Tet1−/−/wild type)) in E12.5 (left) and E14.5 (right) Tet1−/− PGCs. Spearman’s correlation is shown. f, Representative western blot showing TET1 and lamin B protein expression in wild-type, DNMT TKO, and Tet1−/− DNMT TKO mouse ES cells. For all box plots, the upper and lower hinges correspond to the first and third quartiles, the centre line corresponds to the median, and the maxima and minima correspond to the highest or lowest value within 1.5 × the inter-quartile range, respectively.
Extended Data Figure 10 Epigenetic characterization of GRR gene promoters in mouse ES cells.
a, Genomic sequences centred on transcription start sites of GRR genes, non-GRR genes activated in both male and female PGCs between E10.5 and E14.5, and non-GRR methylated and demethylated HCP genes in wild-type mouse ES cells grown in serum-containing medium. Each horizontal line represents one gene; the intensity of red indicates the relative enrichment for the feature shown at the top of each column. The transcription start site and sequences 5 kb upstream and downstream of the transcription start site are shown. b–f, Box plots depicting the combined levels of 5mC and 5hmC (ascertained using WGBS)30 (b); levels of 5hmC (ascertained using Aba–seq)15 (c); levels of TET1 (ChIP–seq data)21 (d); levels of RING1B (ChIP–seq data)38 (e) and levels of H2Aub (ChIP–seq data)37 (f) at the promoters of GRR genes and of other relevant gene sets in wild-type mouse ES cells grown in serum-containing media. For all box plots, the upper and lower hinges correspond to the first and third quartiles, the centre line corresponds to the median, and the maxima and minima correspond to the highest and lowest value within 1.5 × the inter-quartile range, respectively. P values are based on a two-sided Wilcoxon test. g, Metagene plot depicting median levels of H3K4me3 (ChIP–seq data)30 around the transcription start sites of GRR genes (left) and non-GRR HCP genes that are also initially methlylated and subsequently demethylated during PGC reprogramming (right) in wild-type and Tet1−/− mouse ES cells grown in serum-containing medium. P values are based on a paired two-sided Wilcoxon test for the promoter (−1 kb/+500 bp) region.
Extended Data Figure 11 Characterization of GRR gene regulation by PRC1 and 5mC in PGCs and mouse ES cells.
a, Overlap between GRR genes and genes significantly upregulated in E11.5 and/or E12.5 PRC1 CKO PGCs compared with wild-type26. P values based on hypergeometric test. b, Representative western blot showing H2Aub and H2A levels in wild-type or DNMT TKO mouse ES cells after 6 h DMSO treatment, and wild-type or DNMT TKO mouse ES cells after 6 h PRT4165 treatment. c, Classification of GRR genes on the basis of their dependency for 5mC and/or PRC1 reprogramming in mouse ES cells (see Methods).
Extended Data Figure 12 Model.
The timely and efficient activation of GRR genes, involved in the transition from PGC to gonocyte and the correct progression of gametogenesis, requires interactions between promoter CpG density, the initiation of global DNA demethylation, TET1 recruitment, and removal of PRC1-mediated repression. Both DNA demethylation-dependent (safeguarding against aberrant residual and/or de novo promoter DNA methylation) and -independent (such as the potential recruitment of OGT or other transcriptional activators to gene promoters22,28) functions of TET1 are important for GRR gene activation.
Supplementary information
Supplementary Information
This file contains Supplementary Tables 1-6, Supplementary Figure 1 and Supplementary References. (PDF 375 kb)
Supplementary Table 7
This table contains GRR genes, E10 PGC gene FPKM values and differential expression in PGCs and mESCs. (XLSX 24156 kb)
Supplementary Table 8
This table shows differential methylation analysis in PGCs. (XLSX 16215 kb)
Supplementary Table 9
This table shows differential expression of transposable elements in Tet1-KO PGCs. (XLSX 164 kb)
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Hill, P., Leitch, H., Requena, C. et al. Epigenetic reprogramming enables the transition from primordial germ cell to gonocyte. Nature 555, 392–396 (2018). https://doi.org/10.1038/nature25964
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DOI: https://doi.org/10.1038/nature25964
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