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Genome–lamina interactions are established de novo in the early mouse embryo


In mammals, the emergence of totipotency after fertilization involves extensive rearrangements of the spatial positioning of the genome1,2. However, the contribution of spatial genome organization to the regulation of developmental programs is unclear3. Here we generate high-resolution maps of genomic interactions with the nuclear lamina (a filamentous meshwork that lines the inner nuclear membrane) in mouse pre-implantation embryos. We reveal that nuclear organization is not inherited from the maternal germline but is instead established de novo shortly after fertilization. The two parental genomes establish lamina-associated domains (LADs)4 with different features that converge after the 8-cell stage. We find that the mechanism of LAD establishment is unrelated to DNA replication. Instead, we show that paternal LAD formation in zygotes is prevented by ectopic expression of Kdm5b, which suggests that LAD establishment may be dependent on remodelling of H3K4 methylation. Our data suggest a step-wise assembly model whereby early LAD formation precedes consolidation of topologically associating domains.

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Fig. 1: LADs establish de novo after fertilization.
Fig. 2: Single cells within the same developmental stages show consistent LAD patterning and LADs show parental differences.
Fig. 3: Replication unrelated formation of LADs is concordant with A/B compartments and precedes TAD structuring.
Fig. 4: Overexpression of Kdm5b histone demethylase abrogates paternal LAD establishment in the zygote.

Data availability

The sequencing DamID data from this study are available from the Gene Expression Omnibus, accession number GSE112551.

Code availability

Custom code generated to perform the analysis in this study is available upon request.


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We thank members of the J.K. and M.-E.T.-P. laboratories and T. Straub (Biomedical Center, Ludwig-Maximilians-University) for helpful discussions and comments on the manuscript; I. Solovei, A. Scialdone and A. van Oudenaarden for critical reading of the manuscript; J. Gribnau (Erasmus UMC Rotterdam) for providing the embryonic stem cells and J. W. Jachowicz for embryo drawings. We thank R. Tepperino (Helmholtz Centre Munich) for support. We acknowledge funding by ERC-Stg EpiID (678423) to J.K. and EpiGeneSys NoE, ERC-Stg NuclearPotency (280840), the German Research Council (CRC 1064) and the Helmholtz Association to M.-E.T.-P. M.B. held a Boehringer Ingelheim Fonds PhD fellowship. The Oncode Institute is supported by KWF Dutch Cancer Society.

Peer review information

Nature thanks Katsuhiko Shirahige and the other anonymous reviewer(s) for their contribution to the peer review of this work.

Author information




M.B. performed the embryo work, S.M.P. managed the sequencing data and performed all bioinformatic analysis, except for the Hi-C data, which were analysed by M.B. and T.S. and the expression analysis in Extended Data Figs. 1h, 2f, h by E.R.R.-M. J.P. constructed the pipeline for 3D imaging analyses. K.L.d.L. optimized the single-cell DamID protocol. S.S.d.V. designed and performed experiments with the mouse embryonic stem cell DamID lines. M.B. and S.M.P. contributed to experimental design and data interpretation. M.-E.T.-P. and J.K. conceived, designed and supervised the project.

Corresponding authors

Correspondence to Maria-Elena Torres-Padilla or Jop Kind.

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The authors declare no competing interests.

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Extended data figures and tables

Extended Data Fig. 1 Establishment of DamID in mouse pre-implantation embryos.

a, Immunostaining of lamin A/C and lamin B1 in oocytes, zygotes, 2-cell and 8-cell embryos and blastocysts. Scale bars, 5 μm. Levels were previously quantified by western blot in ref. 24. Experiments were repeated at least three times. b, m6ATracer signals with and without auxin. Scale bar, 20 μm. Experiments were repeated at least three times with similar results. c, PCR smears amplified from ten 2-cell embryos injected with varying amounts of mRNA encoding Dam–lamin B1 and developed in the presence or absence of auxin. Experiments were repeated at least three times with similar results. d, Development to the blastocyst in the absence or presence of auxin. e, Development to the blastocyst of zygotes injected with Dam or Dam–lamin B1 mRNA in the absence or presence of auxin. f, Dam–lamin B1 profiles on chromosome 11. Black boxes represent LAD domains. g, Hierarchical clustering of Dam–lamin B1 population (n = 3) and average single cell profiles in oocyte (n = 56), zygote (n = 19), 2-cell (n = 47) and 8-cell stage (n = 42). n = number of biologically independent samples. h, Comparison of genomic profiles obtained by DamID sequencing (this study) to previous DamID on micro-arrays. Black boxes represent LAD domains called by HMM. r = Spearman’s rho. i, Venn diagram showing overlap between LADs in embryonic stem cells, ICM and trophectoderm (TE).

Extended Data Fig. 2 Features of embryonic LADs, analysis of gene expression and oocyte DamID.

a, Left, chromosome plots comparing Dam and Dam–lamin B1 DamID profiles in 2-cell embryos, 8-cell embryos and embryonic stem cells. Right, genome-wide comparison scatter plots of Dam and Dam–lamin B1 scores per 100-kb bin in 2- and 8-cell embryos and embryonic stem cells (right panel). DamID scores were calculated based on n = 3 independent biological replicates. r = Spearman’s rho. b, Average CpG density, AT content and DNaseI hypersensitivity sites (DHS)10 over LAD boundaries. c, Percentage overlap of LADs in embryos with constitutive LADs (associating with the lamina in embryonic stem cells, astrocytes, neural precursor cells and mouse embryonic fibroblasts)8,37. d, CpG density, A/T content, DNase hypersensitivity (DHS) and minor ZGA gene expression at the 2-cell stage in genomic regions reorganizing in respect to the nuclear periphery during the zygote to 2-cell stage transition. Violin plots show the 25th and 75th percentiles (white boxes), median (black horizontal line) and values at most 1.5 × IQR. For CpG density, A/T content and DHS, n = number of bins; for minor ZGA expression, n = number of minor ZGA genes. Wilcoxon rank-sum test P values shown (two-sided). DHS data from ref. 13, expression data from ref. 19. e, Percentage overlap of the de novo iLAD at the 2-cell stage with constitutive LADs (as defined for c). f, Heat map of gene expression Z-scores at different stages of early embryonic development, depicting only genes in LADs specific to the 2-cell stage. These genomic regions contain 957 genes of which the 155 expressed genes are presented in the heat map (see Methods). g, Percentage of minor ZGA genes of total number of genes in iLADs (purple) and LADs (green). h, Example regions of LAD dynamics between the zygote and 2-cell stage (left top) and the 2-cell and 8-cell stage (right top). For each region, the mRNA expression levels are depicted in RPKM (red). The bottom panels display two examples of LAD dynamics between the zygote, 2-cell and 8-cell stages. The location of two genes in the 2-cell-specific LADs is indicated with a dotted line and the expression levels (RPKM) of the corresponding genes is displayed as violin plots. Violin plots show median (black points) and values at most 1.5 × IQR. n = biologically independent samples; zygote (n = 4), 2-cell (n = 10) and 8-cell (n = 28). i, Chromosome plot comparing Dam and Dam–lamin B1 profiles in oocytes and zygotes. j, Chromosome plots comparing Dam and Dam–lamin B1 DamID population and single-cell profiles in oocytes and zygotes.

Extended Data Fig. 3 Chromosome interaction profiles of Dam–lamin B1 triplicate samples.

Dam–lamin B1 chromosomal interaction maps from three biological replicate DamID population samples for each embryonic stage. Coloured blocks represent HMM-called LAD domains. Black bars on the left represent centromeres, red highlights indicate unmappable regions.

Extended Data Fig. 4 Single cells show consistent LAD patterning within the same developmental stages but parental genomes display distinct features.

a, Chromosome profiles of population average (n = 3) and single-cell average Dam–lamin B1 signals. Black boxes represent LAD domains called by HMM. b, Genomic location of example DNA FISH probes projected on Dam–lamin B1 chromosome profiles. c, Quantification of 3D preserved DNA FISH spot distances to the nuclear periphery in 2-cell and 8-cell embryos of probes in regions that change LAD status between 2-cell and 8-cell stages according to DamID. Box plots show the 25th and 75th percentiles (box), median (solid lines), the smallest and largest values within 1.5 × IQR of the hinge (whiskers) and outliers (grey circles). n = number of DNA FISH spots from at least three biologically independent samples. Wilcoxon rank-sum test P values shown (two-sided). **P ≤ 0.01, ****P ≤ 0.0001. d, Images of 3D DNA FISH in zygote pronuclei. Quantification shows distance to the nuclear periphery. Scale bars, 10 μm. Box plots show the 25th and 75th percentiles (box), median (solid lines), the smallest and largest values within 1.5 × IQR of the hinge (whiskers) and outliers (grey circles). n = number of DNA FISH spots from at least three biologically independent samples. e, Distance quantification of DNA FISH probes in maternal and paternal specific LADs in zygotes. Box plots show the 25th and 75th percentiles (box), median (solid lines), the smallest and largest values within 1.5 × IQR of the hinge (whiskers) and outliers (grey circles). n = number of DNA FISH spots from at least three biologically independent samples. Wilcoxon rank-sum test P values shown (two-sided). *P ≤ 0.05, **P ≤ 0.01, ***P ≤ 0.001,**** P ≤ 0.0001. f, t-SNE representation of the triplicate allelic Dam–lamin B1 population samples, including 2-cell embryos from reciprocal crosses. n = 3 biologically independent samples. g, Scatter plot comparison between average Dam–lamin B1 signals obtained from pronucleus separated and hybrid zygote DamID. n = biologically independent samples. Maternal pronucleus (n = 10), paternal pronucleus (n = 15) and hybrid zygote (n = 3). r = Spearman’s rho. h, Average CpG density, AT content and DHS sites over LAD boundaries ± 1.5 Mb defined specifically for maternal and paternal alleles in zygotes. i, Allelic correlation matrix (Pearson) of OE scores form Dam–lamin B1 embryos. j, Jaccard indexes calculated over HMM-called LAD domains.

Extended Data Fig. 5 Compartment status of regions with different LAD dynamics during embryonic development.

a, Violin plots of compartment scores calculated for 100-kb genomic regions with different LAD dynamics. Number in parentheses represents the percentage of the genome covered by each of the 16 different categories of defined LAD reorganizations from zygote to embryonic stem cell. Violin plots show the values at most 1.5 ×  IQR and median (red lines). Compartment scores are calculated based on three biologically independent samples. n = number of 100-kb bins b, Experimental schemes of DamID in aphidicolin-treated zygotes and 2-cell embryos. Images show global DNA replication measured by EdU incorporation in control and replication-inhibited embryos. n = number of images of independent experiments. Scale bars, 10 μm. c, Chromosome plots of compartment scores from Hi-C and DamID scores in control and aphidicoline treated zygotes and 2-cell embryos.

Extended Data Fig. 6 Overexpression of Kdm5b histone demethylase abrogates paternal LAD establishment in the zygote.

a, Quantifications of immunostaining with H3K9me3 in zygotes injected with wild-type and mutant KDM4D. Violin plots show the values at most 1.5 × IQR and median (red lines). n = at least three biologically independent samples. Wilcoxon rank-sum test P values shown (two-sided). b, Average paternal-specific H3K4me3 signal at paternal-specific LAD boundaries of each respective embryonic stage. c, Average maternal specific H3K4me3 signal at maternal specific LAD boundaries of each respective embryonic stage. d, Quantification as described for a but with H3K4me3. e, Immunostaining and quantification of lamin B1 localization in the Kdm5b-expressing zygotes. f, Global transcription detection (EU incorporation) and quantification in H3K4me3 in the Kdm5b-expressing zygotes. g, Immunofluorescent staining of H3K9me3 in mutant and wild-type KDM5B-expressing embryos. h, Immunofluorescent staining of H3K9me2 in mutant and wild-type KDM5B injected embryos. i, Hierarchical clustering based on Pearson correlation of Dam–lamin B1 signal from single pronuclei of wild-type and mutant Kdm5b-injected zygotes (samples from three independent experiments). For comparison, population average Dam and Dam–lamin B1 signals are included as grey and black squares, respectively. j, Average Dam–lamin B1 signal at LAD boundaries in hybrid H3K4me3 manipulated embryos. Signal shown in maternal genome (top) and paternal genome (bottom). k, Chromosome profiles of H3K4me3 ChIP with sequencing (ChIP–seq)20 signal from sperm, early zygotes and late zygotes. l, Average H3K4me3 levels in sperm, early zygotes and late zygotes at paternal zygotic LAD borders. In eh, violin plots show the values at most 1.5 × IQR and median (red lines); Wilcoxon rank-sum test P values shown (two-sided). Scale bars, 10 μm.

Supplementary information

Reporting Summary

Supplementary Table 1

Genomic DNA-FISH coordinates and antibody information.

Supplementary Table 2

scDamID barcoded primers.

Supplementary Table 3

Single-cell and population DamID read counts.

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Borsos, M., Perricone, S.M., Schauer, T. et al. Genome–lamina interactions are established de novo in the early mouse embryo. Nature 569, 729–733 (2019).

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