Fukushima HS , Ikeda T , Ikeda S , Takeda H .

JP23K14121 MEXT | Japan Society for the Promotion of Science (JSPS), JP22K20625 MEXT | Japan Society for the Promotion of Science (JSPS), JP23K14190 MEXT | Japan Society for the Promotion of Science (JSPS), JP18gm1110007h0001 Japan Agency for Medical Research and Development (AMED)

             cell cycle
             cell cycle process
             heterochromatin assembly

	Figure 6. Heterochromatin establishment during the MBT is cell cycle length-dependent in X. laevis. (A) Schematic illustration of X. laevis embryo development before and after the MBT. (B) Immunofluorescence staining of H3K9me3 in control (stage 9 and stage 10) and α-amanitin-injected (stage 10) X. laevis embryo. (C) Quantification of (B). Each dot indicates the average of ~20 cells in a single broad field slice image of single embryo. Two-sided Welch’s t-test. Bars indicate the means. n = 23, 22 and 19 embryos for the control stage 9, control stage 10 and α-amanitin stage 10, respectively. Data were pooled from two independent experiments. (D) Phenotype of α-amanitin-injected X. laevis embryos. Unlike control embryos, α-amanitin-injected embryos failed to form dorsal lip at 10.5 hpf, indicating defects in gastrulation. (E) Schematic summarizing chk1 injection (top) and animal view of chk1-injected X. laevis embryos (bottom). Stages highlighted in green were compared in (F) and (G). To compare developmental stages, cells at the animal poles are shown in magnified views (yellow squares). (F) Immunofluorescence staining of H3 and H3K9me3 in the chk1 injection at the stage 9. (G) Quantification of (F). Each dot indicates the average of ~10 cells in a single broad field slice image of single embryo. Two-sided Wilcoxon rank-sum test. Bars indicate the means. n = 21 and 14 embryos for the control 7 hpf and chk1 9 hpf, respectively. Data were pooled from three independent experiments. ***p < 0.001, NS: not significant. Source data are available online for this figure.
	Figure 7. Cell cycle length governs both erasure and re-establishment of heterochromatin during early development in non-mammalian vertebrates. Schematic summarizing the model of H3K9me3 reprogramming in non-mammalian vertebrates. Cell cycles in fertilized eggs and cleavage embryos are very rapid in non- mammalian vertebrates. This prevents Setdb1 (magenta dots) from accumulating in nuclei, resulting in DNA replication-dependent gradual erasure of H3K9me3 (green intensity in nuclei). However, cell cycles were prolonged from the MBT. Hereafter, Setdb1 can sufficiently accumulate in nuclei during the slowing of cell cycles, increasing H3K9me3 levels in blastula and gastrula embryos.
	Figure 1. Passive erasure of heterochromatin during early cleavage stages in medaka.(A) Development of medaka embryo during early cleavage stages. (hpf: hours post fertilization). (B) Immunofluorescence staining of H3K9me3 during early cleavage stages. (C) Quantification of (B). Each dot indicates the average intensity of 1–2 cells in a single broad field slice image of single embryo. Two-sided Wilcoxon rank-sum test. Bars indicate the means. n = 18, 18, 20, 22, 8 embryos for the 1, 2, 4, 8, and 16-cell stage, respectively. Data were pooled from three independent experiments. (D) Schematic summarizing the chk1 experiment (top) and the proportion of stages in the chk1 experiment in medaka (bottom). Stages highlighted in green and blue were compared in (E) and (F). (E) Immunofluorescence staining of H3K9me3 in the chk1 experiment. (F) Quantification of (E). Each dot indicates the average intensity of 1–2 cells in a single broad field slice image of single embryo. Two-sided Wilcoxon rank-sum test. Bars indicate the means. n = 16, 34, 13 embryos for the control 1.2 hpf, control 2.1 hpf and chk1 2.1 hpf, respectively. Data were pooled from three independent experiments. *p < 0.05, **p < 0.01, ***p < 0.001, NS: not significant. Source data are available online for this figure.
	Figure 2. ZGA is dispensable for heterochromatin establishment during the MBT in medaka.(A) Development of medaka embryos before and after the MBT. (B) Phenotype of α-amanitin-injected medaka embryos. (C) Immunofluorescence staining of H3K9me3 at the late blastula stage (8.5 hpf) in the α-amanitin injection experiment. (D) Quantification of (C). Each dot indicates the average intensity of ~40 cells in a single broad field slice image of single embryo. Two-sided unpaired Student’s t-test. Bars indicate the means. n = 20 embryos. Data were pooled from two independent experiments. (E) Western blot of H3K9me3 and GAPDH using control and α-amanitin-injected embryos at the late blastula stage (8.5 hpf). (F) Quantification of (E). H3K9me3 signal intensity was normalized by GAPDH signal intensity. Two-sided unpaired Student’s t-test. Error bars indicate the mean ± s.d. n = 3 biological replicates. (G) DAPI-staining at the late morula and late blastula stages. Colormaps are shown at the bottom to better illustrate the appearance of DNA-dense regions at the late blastula stage. (H) Quantification of DNA contrast in (G). Each dot indicates the DNA contrast of a single nucleus. ~6 embryos were analyzed. Two-sided Wilcoxon rank-sum test. Bars indicate the means. n = 15 and 30 nuclei for the late morula and late blastula, respectively. Data were pooled from two independent experiments. (I) DAPI and immunofluorescence staining of embryos injected with human KDM4D, a demethylase of H3K9me3, or its catalytically inactive mutant KDM4D(H192A) at the late blastula stage. The pattern of DNA-dense domains was comparable irrespective of presence or absence of H3K9me3. (J) Quantification of DNA contrast in (I). Each dot indicates the DNA contrast of a single nucleus. Five embryos were analyzed. Two-sided unpaired Student’s t-test. Bars indicate the means. n = 22 and 24 nuclei for the KDM4D(H192A) and KDM4D, respectively. Data were pooled from two independent experiments. ***p < 0.001, NS: not significant. Source data are available online for this figure.
	Figure 3. Cell cycle slowing regulates heterochromatin establishment during the MBT in medaka.(A) Schematic summarizing the chk1 experiment (top) and the proportion of stages in the chk1 experiment in medaka (bottom). Stages highlighted in blue were compared in (B) and (C). (B) Immunofluorescence staining of H3K9me3 and γH2AX at the late morula stage in the chk1 injection experiment. (C) Quantification of (B). Each dot indicates the average of 30–40 cells in a single broad field slice image of single embryo. Two-sided Welch’s t-test and two-sided unpaired Student’s t-test were performed for H3K9me3 and γH2AX, respectively. Bars indicate the means. n = 19 and 14 embryos for the control 5.5 hpf and chk1 8.5 hpf, respectively. Data were pooled from two independent experiments. (D) Schematic summarizing CHX treatment (top) and proportion of stages in CHX treatment in medaka (bottom). Stages highlighted in green were compared in (E) and (F). (E) Immunofluorescence staining of H3K9me3 and γH2AX in CHX treatment at the 16-cell stage. (F) Quantification of (E). Each dot indicates the average of ~5 cells in a single broad field slice image of single embryo. Two-sided Welch’s t-test and two-sided Wilcoxon rank-sum test were performed for H3K9me3 and γH2AX, respectively. Bars indicate the means. n = 15 and 11 embryos for the DMSO 2.8 hpf and CHX 3.5 hpf, respectively. Data were pooled from three independent experiments. (G) Schematic showing counting of nuclei in an embryo (left) and the number of cells per embryo in the H3-tail injection experiment (8.5 hpf) (right). Two-sided unpaired Student’s t-test. Bars indicate the means. n = 10 and 12 embryos for the control 8.5 hpf and H3-tail 8.5 hpf, respectively. Data were pooled from two independent experiments. (H) Immunofluorescence staining of H3K9me3 in H3-tail injection (8.5 hpf). (I) Quantification of (H). Each dot indicates the average intensity of ~140 cells in a single broad field slice image of single embryo. Two-sided unpaired Student’s t-test. Bars indicate the means. n = 9 and 14 embryos for the control 8.5 hpf and H3-tail 8.5 hpf, respectively. Data were pooled from two independent experiments. *p < 0.05, **p < 0.01, ***p < 0.001, NS: not significant. Source data are available online for this figure.
	Figure 4. Setdb1 accumulates to nuclei upon the MBT in medaka.(A) Immunofluorescence staining of Setdb1 in medaka embryos before (late morula) and after the MBT (late blastula and pre-early gastrula). Signal intensities along the yellow arrows were quantified in (B). (B) Quantification of signal intensity of DAPI and Setdb1 along the yellow arrows in (A). (C) Quantification of nuclear/cytoplasmic ratio (N/C ratio) of Setdb1 in medaka embryos before (late morula) and after the MBT (late blastula and pre-early gastrula). Each dot indicates the N/C ratio of a single cell. 10, 8, and 10 embryos at the late morula, late blastula, and pre-early gastrula, respectively, were analyzed. Two-sided Wilcoxon rank-sum test. Bars indicate the means. n = 59, 142, and 193 cells for the late morula, late blastula, and the pre-early gastrula stage, respectively. Data were pooled from three independent experiments. (D) Schematic showing chk1 overexpression experiment (top) and quantification of N/C ratio of Setdb1 in control and chk1-injected embryos (bottom) at the late morula stage. Each dot indicates the N/C ratio of a single cell. Eleven embryos were analyzed for each condition. Two-sided Wilcoxon rank-sum test. Bars indicate the means. n = 69 and 55 cells for the control 5.5 hpf and chk1 8.5 hpf, respectively. Data were pooled from two independent experiments. (E) Schematic representation of the model of Setdb1 accumulation induced by cell cycle slowing during the MBT. ***p < 0.001. Source data are available online for this figure.
	Figure 5. Heterochromatin establishment during the MBT is cell cycle length-dependent in zebrafish.(A) Development of zebrafish embryo before and after the MBT. (B) Immunofluorescence staining of H3K9me3 in zebrafish embryos before (64-cell) and after the MBT (Sphere). (C) Quantification of (B). Each dot indicates the average of ~5 and ~60 cells in a single broad field slice image of single embryo at the 64-cell stage and the sphere stage, respectively. Two-sided Welch’s t-test. Bars indicate the means. n = 16 and 22 embryos for the 64-cell and sphere stage, respectively. Data were pooled from two independent experiments. (D) Phenotype of α-amanitin-injected zebrafish embryos. (E) Immunofluorescence staining of H3K9me3 in the α-amanitin injection experiment at the sphere stage. (F) Quantification of (C). Each dot indicates the average of ~60 cells in a single broad field slice image of single embryo. Two-sided Wilcoxon rank-sum test. Bars indicate the means. n = 11 and 13 embryos for the control and α-amanitin, respectively. Data were pooled from two independent experiments. (G) Schematic summarizing the CHX experiment (top) and the proportion of stages of CHX-treated zebrafish embryos (bottom). Stages highlighted in green were compared in (H) and (I). (H) Immunofluorescence staining of H3K9me3 and γH2AX in CHX treatment at the 64-cell stage. (I) Quantification of (H). Each dot indicates the average of ~2 cells in a single broad field slice image of single embryo. Two-sided Wilcoxon rank-sum test. Bars indicate the means. n = 17 and 26 embryos for the DMSO 2 hpf and CHX 2.75 hpf, respectively. Data were pooled from two independent experiments. ***p < 0.001, NS: not significant. Source data are available online for this figure.
	Figure EV1. Supportive data for Fig. 1.(A) Development of medaka embryos at the one-cell stage. Blue and magenta indicate paternal and maternal pronuclei, respectively. mpf: minutes post fertilization. (B) Immunofluorescence staining of H3K4me3 at the one-cell stage. The number of embryos with the representative pattern is indicated at the bottom. (C) Immunofluorescence staining of H3K4me3 at the 2-cell stage in the chk1 experiment. Yellow dashed line indicates nuclei. The number of embryos with the representative pattern is indicated at the bottom.
	Figure EV2. Supportive data for Fig. 2.(A) Procedure of analyzing zygotic expression level in α-amanitin-injected embryos using previous dataset (Nakamura et al, 2021). The number of RNA-seq biological replicate is n = 2 and 1 for normal embryos and hybrid embryos, respectively. See Methods for the detail. (B) Scatterplot indicates that α-amanitin injection impaired zygotic expression at the pre-early gastrula stage in medaka. Previous dataset (Nakamura et al, 2021) was analyzed as shown in (A) and Methods. (C) Procedure of quantification of relative amount of DNA per embryo (left) and the results (right) at the late blastula stage. Two-sided unpaired Student’s t-test. Error bars indicate the mean ± s.d. n = 4 biological replicates. (D) Immunofluorescence staining of H3K9me3 in α-amanitin-injected medaka embryos at the pre-early gastrula stage. (E) Quantification of (D). Each dot indicates the average intensity of ~50 cells in a single broad field slice image of single embryo. Two-sided Welch’s t-test. Bars indicate the means. n = 18 and 19 embryos for the control and α-amanitin, respectively. Data were pooled from two independent experiments. (F) Uncropped results of quantitative western blot at the late blastula stage using anti-GAPDH and anti-H3K9me3 antibodies. Magenta arrows indicate the specific bands. (G) Quantification of western blot signal intensities in Figs. 1F and EV2F. Scatter plots show that all signal intensities of western blots were within the linear range. (H) DAPI staining of control or α-amanitin-injected embryos at the late blastula stage. (I) Quantification of (H). Each dot indicates the DNA contrast of a single nucleus. Ten embryos were analyzed. Two-sided unpaired Student’s t-test. Bars indicate the means. n = 53 and 59 nuclei for the late morula and late blastula, respectively. Data were pooled from two independent experiments. ***p < 0.001, NS: not significant.
	Figure EV3. Supportive data for Fig. 3.(A) Number of cells per embryo at 3.5–10.5 hpf counted by Imaris software using DAPI staining data. n = 5, 3, 4, 4, 4, 4, 2 embryos for each stage. (B) Number of post fertilization cell-cycles estimated by total number of cells per embryo in (A). n = 5, 3, 4, 4, 4, 4, 2 embryos for each stage. (C) Cell cycle length estimated by cell cycle number and time line in (B). (D) Immunofluorescence staining of H3K9me3 in the chk1 injection experiment at the 8-cell stage (2.3 hpf). (E) Quantification of (D). Each dot indicates the average of single cells in a single broad field slice image of single embryo. Two-sided unpaired Student’s t-test was performed. Bars indicate the means. n = 9 and 8 embryos for the control 2.3 hpf and chk1 2.3 hpf, respectively. Data were pooled from two independent experiments. (F) Schematic summarizing H3-tail injection (top) and proportion of stages of H3-tail-injected embryos in the cleavage stages (bottom). (G) Immunofluorescence staining of H3K9me3 and γH2AX in control and UV-treated embryos at the late blastula stage. (H) Quantification of (G). Each dot indicates the average of ~100 cells in a single broad field slice image of single embryo. Two-sided unpaired Student’s t-test. Bars indicate the means. n = 17 and 13 embryos for the control and UV exposure, respectively. Data were pooled from two independent experiments. (I) Schematics summarizing RNA sampling (top) and RT-qPCR of zygotic genes (bottom). Expression level was first normalized by that of actb in each sample and subsequently normalized by the average expression level in control 8.5 hpf. Stages highlighted in blue or green were compared. Two-sided Welch’s t-test. Error bars indicate the mean ± s.d. n = 3 biological replicates. *p < 0.05, **p < 0.01, ***p < 0.001, NS: not significant.
	Figure EV4. Supportive data for Fig. 4.(A) Expression level of H3K9me3 methyltransferases and demethylases during early development. Data was obtained from previous RNA-seq data (Nakamura et al, 2021; Ichikawa et al, 2017). (B) Domains of Setdb1 and amino acid sequence in the SET domain. The antigen sequence of the anti-Setdb1 antibody (sc-166621) is highlighted in magenta. (C) Schematic of the experiments to validate the specificity of the anti-Setdb1 antibody (sc-166621) (left) and the results of western blot at the late blastula stage (right). Blue, magenta, and green arrows indicate endogenous Setdb1b, exogenously expressed FLAG-Setdb1b, and exogenously expressed FLAG-Suv39h1b, respectively. Asterisks (*) indicate non-specific bands. (D) Schematic of the experiments to validate the localization of exogenously expressed FLAG-Suv39h1 and FLAG-Setdb1 (left) and immunofluorescence staining against anti-FLAG at the late morula stage (right). Consistent with the Fig. 4, exogenously overexpressed FLAG-Setdb1 localized to cytoplasm, while FLAG-Suv39h1 mainly accumulated in nuclei. The number of embryos with the representative pattern is indicated at the bottom.
	Figure EV5. Supportive data for Figs. 5 and 6.(A) Schematic of counting nuclei in an embryo using a single slice (left) and the cell number in α-amanitin-injected zebrafish embryos at the sphere or dome stage (right). Two-sided unpaired Student’s t-test. Bars indicate the means. n = 11, 13, 13, and 17 embryos for the sphere control, sphere α-amanitin, dome control, and dome α-amanitin, respectively. Data were pooled from two independent experiments. (B) Procedure of quantification of the relative amount of DNA per embryo (left) and the results (right) in α-amanitin-injected zebrafish embryos at the dome stage. Two-sided Welch’s t-test. Error bars indicate the mean ± s.d. n = 11 biological replicates. (C) Immunofluorescence staining of H3K9me3 in α-amanitin injection experiment at the dome stage. (D) Quantification of (C). Each dot indicates the average of ~80 cells in a single broad field slice image of single embryo. Two-sided unpaired Student’s t-test. Bars indicate the means. n = 13 and 17 embryos for the control and α-amanitin, respectively. Data were pooled from two independent experiments. (E) Uncropped results of quantitative western blot at the dome stage using anti-H3K9me3 antibody. The Magenta arrow indicates the specific bands. The same number of dome-stage embryos (1× = ~3.5 embryos/lane) were loaded into each lane to compare total H3K9me3 levels per embryo. (F) Quantification of western blot signal intensities in (E). Scatter plots show that all western blot signal intensities were within the linear range. (G) Quantification of (E). On the right, data after normalization by the DNA ratio measured in Fig EV5B. Error bars indicate the mean ± s.d. n = 4 biological replicates. (H) Schematic summarizing the CHX treatment (top) and animal view of CHX-treated X. laevis embryos (bottom). Stages highlighted in green were compared in (I) and (J). To compare developmental stages, cells at the animal poles are magnified (yellow squares). (I) Immunofluorescence staining of H3 and H3K9me3 in CHX treatment at the stage 9. (J) Quantification of (I). Each dot indicates the average of ~5–10 cells in a single broad field slice image of single embryo. Two-sided Welch’s t-test. Bars indicate the means. n = 18 and 19 embryos for the DMSO 7 hpf and CHX 9 hpf, respectively. Data were pooled from two independent experiments. *p < 0.05, **p < 0.01, NS: not significant.

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