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EMBO Rep
2024 Jun 28; doi: 10.1038/s44319-024-00188-5.
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Cell cycle length governs heterochromatin reprogramming during early development in non-mammalian vertebrates.
Fukushima HS
,
Ikeda T
,
Ikeda S
,
Takeda H
.
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Heterochromatin marks such as H3K9me3 undergo global erasure and re-establishment after fertilization, and the proper reprogramming of H3K9me3 is essential for early development. Despite the widely conserved dynamics of heterochromatin reprogramming in invertebrates and non-mammalian vertebrates, previous studies have shown that the underlying mechanisms may differ between species. Here, we investigate the molecular mechanism of H3K9me3 dynamics in medaka (Japanese killifish, Oryzias latipes) as a non-mammalian vertebrate model, and show that rapid cell cycle during cleavage stages causes DNA replication-dependent passive erasure of H3K9me3. We also find that cell cycle slowing, toward the mid-blastula transition, permits increasing nuclear accumulation of H3K9me3 histone methyltransferase Setdb1, leading to the onset of H3K9me3 re-accumulation. We further demonstrate that cell cycle length in early development also governs H3K9me3 reprogramming in zebrafish and Xenopus laevis. Together with the previous studies in invertebrates, we propose that a cell cycle length-dependent mechanism for both global erasure and re-accumulation of H3K9me3 is conserved among rapid-cleavage species of non-mammalian vertebrates and invertebrates such as Drosophila, C. elegans, Xenopus and teleost fish.
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)
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.
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