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The DNA methylation landscape of human early embryos

Abstract

DNA methylation is a crucial element in the epigenetic regulation of mammalian embryonic development1,2,3,4,5. However, its dynamic patterns have not been analysed at the genome scale in human pre-implantation embryos due to technical difficulties and the scarcity of required materials. Here we systematically profile the methylome of human early embryos from the zygotic stage through to post-implantation by reduced representation bisulphite sequencing and whole-genome bisulphite sequencing. We show that the major wave of genome-wide demethylation is complete at the 2-cell stage, contrary to previous observations in mice. Moreover, the demethylation of the paternal genome is much faster than that of the maternal genome, and by the end of the zygotic stage the genome-wide methylation level in male pronuclei is already lower than that in female pronuclei. The inverse correlation between promoter methylation and gene expression gradually strengthens during early embryonic development, reaching its peak at the post-implantation stage. Furthermore, we show that active genes, with the trimethylation of histone H3 at lysine 4 (H3K4me3) mark at the promoter regions in pluripotent human embryonic stem cells, are essentially devoid of DNA methylation in both mature gametes and throughout pre-implantation development. Finally, we also show that long interspersed nuclear elements or short interspersed nuclear elements that are evolutionarily young are demethylated to a milder extent compared to older elements in the same family and have higher abundance of transcripts, indicating that early embryos tend to retain higher residual methylation at the evolutionarily younger and more active transposable elements. Our work provides insights into the critical features of the methylome of human early embryos, as well as its functional relation to the regulation of gene expression and the repression of transposable elements.

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Figure 1: Dynamics of the DNA methylome in human early embryos.
Figure 2: Key features of gamete-specific differentially methylated regions (DMRs).
Figure 3: Relationships between DNA methylation, histone modifications and gene expression.
Figure 4: Dynamics of DNA methylation and expression patterns of transposable elements.

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Gene Expression Omnibus

Data deposits

All sequencing data were deposited at the NCBI Gene Expression Omnibus (GEO) under accession number GSE49828.

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Acknowledgements

F.T. and J.Q. were supported by grants from the National Basic Research Program of China (2012CB966704, 2011CB944504 and 2011CB966303) and from the National Natural Science of China (31322037, 31230047, 31271543 and 81170538). J.Q. and F.T. were supported by a grant from the Beijing Municipal Science and Technology Commission (Z131100005213006). L.Y. was supported by grants from the National Natural Science Foundation of China (81000275) and National Basic Research Program of China (2011CB944503). R.L. was supported by a grant from National Key Technologies Research and Development Program (2012BAI32B01).

Author information

Authors and Affiliations

Authors

Contributions

F.T. and J.Q. conceived the experiments and supervised the project. H.G., L.Y., R.L., Y.L. J.Y., X.R., S.L., J.L., X.J., X.S., P.L., X.W., W.W., Y.W., X.L., F.G., X.W., X.F., J.Y. and L.W. performed the experiments. P.Z and B.H. did all of the bioinformatic analyses. S.X.X., J.Q. and F.T. wrote the manuscript with help from all of the authors.

Corresponding authors

Correspondence to Fuchou Tang or Jie Qiao.

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Competing interests

The authors declare no competing financial interests.

Extended data figures and tables

Extended Data Figure 1 DNA methylation dynamics during human early embryonic development.

a, Morphology of human early embryos used in this study. The microscopy images of laser assisted biopsy of polar bodies (PB), mature oocytes, and the first polar bodies, zygotes, 2-, 4-, 8-cell stage embryos, morula, inner cell mass (ICM) and trophectoderm cells (TE) from blastocyst stage embryos. Notably, the zonapellucida of all embryos, as well as mature oocytes, is removed to avoid any possible contaminants. Scale bar, 50 μm. b, Pearson correlation heat map of DNA methylomes at different developmental stages of human early embryos. The numbers in the sample names indicate different biological replicates of the same developmental stages. The colour key from green to red indicates the correlation coefficient from low to high, respectively. c, The averaged non-CpG DNA methylation levels of MII oocytes, the first (1st PB) and second (2nd PB) polar bodies, along the gene bodies and 15 kb upstream of the transcription start sites (TSS) and 15 kb downstream of the transcription end sites (TES) of all RefSeq genes. d, Non-CpG methylation levels across different human early embryonic stages. The red bars indicate the averaged DNA methylation levels of the non-CpG sites (CHG and CHH), while the grey bars indicate the bisulphite non-conversion rate of corresponding samples. All data are mean ± 95% confidence interval (± 1.96 s.e.m.). Details of biological replicates of each stage are listed in Supplementary Table 1. e, The positive correlation of non-CpG methylation levels of the gene bodies and the expression levels of corresponding genes in MII oocytes, R indicates the Pearson correlation coefficient.

Extended Data Figure 2 The general characteristics of the DNA methylation patterns during human early embryonic development.

a, The heat map view of a representative section of chromosome 1 showing the dynamics of DNA methylomes across different developmental stages. The green bars in the right panel indicate the average methylation levels of the corresponding regions. And the window size for the DNA methylation level calculation and presentation of these green bars is the single CpG dinucleotide covered (at least five times) in these corresponding regions. b, Histogram of the numbers of changing (royal blue) and stable (sky blue) tiles between consecutive stages, which shows the major transitions in DNA methylation levels during human early embryonic development. c, Histogram of the numbers of DNA tiles showing increasing (magenta) and decreasing (cyan) levels of DNA methylation between consecutive stages of human early embryos. d, Histogram of the fractions of tiles with 0–20%, 20–40%, 40–60%, 60–80% and 80–100% methylation levels across different developmental stages. e, The distribution of high/intermediate (methylation level ≥ 0.2) and low (methylation level < 0.2) methylation tiles at each developmental stage against CpG density. f, Histogram of the counts of 100 bp tiles with different methylation levels. n means the total number of the 100 bp tiles for each stage. g, Box plots of methylation levels of each stage across local CpG densities.

Extended Data Figure 3 The dynamic changes of DNA methylation on a variety of annotated genomic regions.

a, Histograms of the numbers of tiles with increasing (magenta) and decreasing (cyan) DNA methylation between each pair of consecutive stages in the annotated genomic regions during human early embryonic development. b, The line charts of the average methylation levels of annotated genomic regions during human early embryonic development. The green dot at gamete stage indicates the average DNA methylation levels of the corresponding regions in sperm, while the purple dot at gamete stage indicates those in MII oocytes. HCP, high-density CpG promoter; ICP, intermediate-density CpG promoter; LCP, low-density CpG promoter; annotations as previously published20. All data are mean ± 95% confidence interval (± 1.96 s.e.m.). Details of biological replicates are listed in Supplementary Table 1.

Extended Data Figure 4 DNA methylation patterns in oocytes, polar bodies, sperm, blastocysts and post-implantation embryos.

a, Histograms of the averaged DNA methylation levels of sperm (n = 4), ICM of blastocysts (n = 3), and post-implantation embryos (liver, n = 3) covered by both RRBS and WGBS data sets (WGBS data set of sperm was downloaded from Molaro, A. et al.26). b, Comparison of the averaged DNA methylation levels along the gene bodies and 15 kb upstream of the transcription start sites (TSS) and 15 kb downstream of the transcription end sites (TES) of all RefSeq genes, respectively. It was analysed by WGBS for sperm (yellow line, WGBS data set of sperm was downloaded from Molaro, A. et al.26), ICM of blastocysts (purple line) and post-implantation embryos (liver; black line). c, Histograms of the average methylation levels in different genomic regions in MII oocytes (n = 2) as well as the first and second polar bodies (the first polar bodies, n = 2; the second polar bodies, n = 2). d, Histograms of the average methylation levels in different genomic regions in ICM (n = 3) and TE (n = 3) isolated from the late blastocysts. All data in panel a, c and d are mean ± 95% confidence interval (± 1.96 s.e.m.).

Extended Data Figure 5 The demethylation patterns of maternal and paternal genomes on a variety of annotated genomic regions.

a, Pearson correlation heat map of DNA methylomes of individual male and female pronuclei as well as the gametes. The colour key from green to red indicates the correlation coefficient from low to high, respectively. The unsupervised clustering result shows that the single male pronuclei and sperm clustered together, while the single female pronuclei and MII oocytes clustered together. b, Discrimination of individual male and female pronuclei by analysing MII oocyte-specific and sperm-specific DMRs. The sperm-specific DMRs (17,096 100 bp tiles) and MII oocyte-specific DMRs (11,850 100 bp tiles) covered by single-cell RRBS data set were used as the criterion for judging individual male and female pronuclei isolated from the same zygotes. The colour key from green to red indicates the DNA methylation levels from low to high, respectively. c, Demethylation dynamics of maternal and paternal genomes in human zygotes analysed by single pronucleus RRBS analysis in different annotated genomic regions.

Extended Data Figure 6 DNA demethylation patterns in pronuclear stage embryos analysed by immunostaining.

a–f, The immunostaining of 5mC, 5hmC and H3K9me3 in human oocytes (a), zygotes (2PN) (b–e) and 2-cell embryos (f). The green and red signals identified from the staining indicate the 5hmC and 5mC modifications, respectively (a, c–f). Male and female symbols in the merged panels indicate the male and female pronuclei. The white triangle symbols indicate the polar bodies. b, The immunostaining of 5mC and H3K9me3 in human zygotes. Human zygotes were co-stained with 5mC (red) and H3K9me3 (green, pronuclei with intense H3K9me3 signals were female pronuclei). g, The immunostaining of 5mC and 5hmC in mouse zygotes and 2-cell embryos as controls. The green and red signals identified from the staining indicate the 5hmC and 5mC modifications, respectively. Male and female symbols in the merged panels indicate the male and female pronucleus. The white triangle symbols indicate the polar bodies.

Extended Data Figure 7 DNA methylation changes of DMR regions and non-DMR regions of the human gametes during pre- and post-implantation embryonic development.

a, Box plots of DNA methylation levels for hypermethylated 100 bp tiles (average methylation levels ≥ 75%) in both gametes across early embryonic development stages. b, Box plots of DNA methylation levels for hypomethylated 100 bp tiles (average methylation levels ≤ 25%) in both gametes across early embryonic development stages. c, The hypergeometric enrichment analysis of the hypermethylated and hypomethylated tiles in both gametes, exhibited the strong enrichment for different genomic regions (hypergometric enrichment test). d, Box plot of methylation levels of oocyte-specific DMRs across different developmental stages. e, Box plot of methylation levels of sperm-specific DMRs across different developmental stages. f, The bar plot showing the numbers of gamete-specific DMRs located in different genomic regions, which indicates the strong enrichment for different regions in sperm-specific DMRs (blue bars) and oocyte-specific DMRs (red bars).

Extended Data Figure 8 The DNA methylation patterns of imprinting genes and ASM regions during human early embryonic development.

a, A representative locus of a known paternal imprinting gene, H19, covered in our RRBS data set. The blue bars indicate the DNA methylation levels of different CpG sites. The region was unmethylated in MII oocytes, fully methylated in sperm cells and around 50% methylated in cleavage embryos and post-implantation embryos. b, A representative locus of a potential novel imprinting region within the gene body of IFI6, covered in our RRBS data set, which was fully methylated in MII oocytes, unmethylated in sperm, around 50% methylated in cleavage embryos and post-implantation embryos. c, d, Two allele-specific methylation loci on chromosome 16 (c) and chromosome 2 (d), tracked with heterozygous SNPs to distinguish their allele origins. The paired reads generated from the WGBS data sets with heterozygous SNPs were selected to show the DNA methylation levels of the two alleles.

Extended Data Figure 9 The relationship of DNA methylation, histone modification and RNA expression during human early embryonic development.

ac, The correlation between signal intensities of three types of histone marks (H3K27me3, in panel a; H3K9me3, in panel b and H3K4me3, in panel c) and the DNA methylation levels of corresponding peak regions during human early embryonic development. The horizontal axis from left to right of each panel represents the peak regions of histone modifications, ranked by their signal intensities from high to low. d, The scatter plot of DNA methylation levels of promoter regions (HCP, ICP and LCP) and the relative expression levels of corresponding RefSeq genes. Log2 values of the gene expression levels (RPKM) are given. The Pearson correlation coefficients (r) between DNA methylation levels of promoter regions and the scaled expression levels of the corresponding genes across different early embryonic stages were calculated and are shown in the top right corner of each panel. The red and blue fitting curves represent gene expression levels and DNA methylation levels of corresponding promoter regions, respectively. The genes were arranged according to their expression levels. e, The scatter plot of DNA methylation levels of gene bodies and the relative expression levels of corresponding RefSeq genes. Log2 values of the gene expression levels (RPKM) are given. The Pearson correlation coefficients (r) between DNA methylation levels of gene body regions (blue lines) and the scaled expression levels (red lines) of the corresponding genes across different early embryonic stages were calculated and are included in the top right corner of each panel. The red and blue fitting curves represent gene expression levels and DNA methylation levels in corresponding gene body regions, respectively. The genes were arranged according to their expression levels. f, Histograms of the average DNA methylation levels in different genomic regions between ICM replicates (n = 3) and human ES cells (GSM822615, n = 2) by RRBS, which showed generally higher methylation levels in human ES cells than the ICM of the blastocysts. All data are mean ± 95% confidence interval (± 1.96 s.e.m.).

Extended Data Figure 10 The relationship of DNA methylation and RNA expression of transposable elements during human pre- and post-implantation embryonic development.

a, The line chart of the relative expression levels (sequencing read counts, normalized by total mappable RefSeq read counts) of SVAs. Notably, the expression levels of SVAs increased dramatically from 4-cell stage to morula stage. Biological replicates in panel a: MII oocyte (n = 3), zygote (n = 3), 2-cell (n = 6), 4-cell (n = 12), 8-cell (n = 20), morula (n = 14), ICM (n = 10), post-implantation (n = 3). b, The average DNA methylation levels of SVAs. The green dot in gamete stage indicates the average DNA methylation level of the corresponding regions in sperm, while the purple dot in gamete stage indicates that in MII oocytes, respectively. Details of biological replicates of each stage are listed in Supplementary Table 1. c, The line chart of the relative expression levels (sequencing read counts, normalized by total mappable RefSeq read counts) of four major subfamilies (ERV1, ERVK, ERVL and ERVL-MaLR) of LTRs during early embryonic development. Biological replicates in panel c: MII oocyte (n = 3), zygote (n = 3), 2-cell (n = 6), 4-cell (n = 12), 8-cell (n = 20), morula (n = 14), ICM (n = 10), post-implantation (n = 3). d, The average DNA methylation levels of four major subfamilies of LTRs during early embryonic development. The green dot in gamete stage indicates the average DNA methylation level of the corresponding regions in sperm, while the purple dot in gamete stage indicates that in MII oocytes. Details of biological replicates of each stage are listed in Supplementary Table 1. e, DNA methylation levels of the subfamilies of Alu, including AluY (the evolutionarily youngest one, the left panel), AluS (the middle panel) and AluJ (the evolutionarily oldest one, the right panel). Details of biological replicates of each stage are listed in Supplementary Table 1. f, DNA methylation levels of the subfamilies of L1, including L1PA (the evolutionarily youngest one in L1 family), L1PB, L1MA, L1MB, L1MC, L1MD and L1ME (the evolutionarily oldest one in L1 family). The green and red dots represented sperm and MII oocytes, respectively. Details of biological replicates of each stage are listed in Supplementary Table 1. g, Histograms of expression levels (RPKM) of DNA methylation-related genes across different human early embryonic stages, including DNA-demethylation-related genes TET1,TET2,TET3 and TDG, as well as DNA-methylation-related genes DNMT1, UHRF1, DNMT3A, DNMT3B and DNMT3L. Biological replicates in panel g: MII oocyte (n = 3), zygote (n = 3), 2-cell (n = 6), 4-cell (n = 12), 8-cell (n = 20), morula (n = 16), blastocyst (n = 30). All data in panel ag are mean ± 95% confidence interval ( ± 1.96 s.e.m.).

Supplementary information

Supplementary Table 1

Summary of the numbers of embryos or cells of each biological replicate used for the RRBS analysis in this study. (XLS 21 kb)

Supplementary Table 2

Summary of the sequencing qualities, reads mapping, and the covered CpG sites and their mean coverage depths at 1×, 5×, and 10× in each stage of the RRBS dataset. The right-hand column shows the average bisulfite conversion rate of each stage. (XLS 23 kb)

Supplementary Table 3

Summary of the sequencing qualities, reads mapping, and the covered CpG sites and their mean coverage depths at 1×, 5×, and 10× of each single cell RRBS and WGBS samples. The right-hand column shows the average bisulfite conversion rate of each stage. (XLS 28 kb)

Supplementary Table 4

The list of the filtered ASM regions covered in our WGBS of post-implanted liver tissue, including the chromosome positions, called SNPs positions, SNP genotypes, and the chromosome locations of the allele specific methylation regions. (XLS 34 kb)

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Guo, H., Zhu, P., Yan, L. et al. The DNA methylation landscape of human early embryos. Nature 511, 606–610 (2014). https://doi.org/10.1038/nature13544

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