Metabolic control of histone acetylation for precise and timely regulation of minor ZGA in early mammalian embryos
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE185653 | GEO | 2022/10/05
REPOSITORIES: GEO
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Project description:Zygotic genome activation (ZGA) is the first transcription event in life. However, it is unclear how RNA polymerase is engaged in initiating ZGA in mammals. Here, by developing small-scale Tn5-assisted chromatin cleavage with sequencing (Stacc–seq), we investigated the landscapes of RNA polymerase II (Pol II) binding in mouse embryos. We found that Pol II undergoes ‘loading’, ‘pre-configuration’, and ‘production’ during the transition from minor ZGA to major ZGA. After fertilization, Pol II is preferentially loaded to CG-rich promoters and accessible distal regions in one-cell embryos (loading), in part shaped by the inherited parental epigenome. Pol II then initiates relocation to future gene targets before genome activation (pre-configuration), where it later engages in full transcription elongation upon major ZGA (production). Pol II also maintains low poising at inactive promoters after major ZGA until the blastocyst stage, coinciding with the loss of promoter epigenetic silencing factors. Notably, inhibition of minor ZGA impairs the Pol II pre-configuration and embryonic development, accompanied by aberrant retention of Pol II and ectopic expression of one-cell targets upon major ZGA. Hence, step-wise transition of Pol II occurs when mammalian life begins, and minor ZGA has a key role in the pre-configuration of transcription machinery and chromatin for genome activation.
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Project description:Histone acetylation H3K27ac is a well-established chromatin marker for active enhancers and promoters. However, reprogramming dynamics of H3K27ac during maternal-to-zygotic transition (MZT) in mammalian embryos has not been well studied. By profiling the allelic landscape of H3K27ac during mouse MZT, here we show that H3K27ac undergoes three waves of rapid global transitions from oocyte to 2-cell stages. Notably, germinal vesicle (GV) oocyte and zygote are globally hyperacetylated by forming noncanonical broad H3K27ac domains that correlate with broad H3K4me3 and open chromatin. H3K27ac also marks genomic regions primed for activation including ZGA gene promoters, retrotransposons, and active alleles of imprinted genes. Importantly, both CBP/p300 and HDAC activities play important roles in regulating the H3K27ac dynamics and are essential for pre-implantation development. Specifically, CBP/p300 deposits broad H3K27ac domains in zygotes and open condensed chromatin at putative enhancers to ensure proper ZGA. In contrast, HDACs mediate the broad to canonical H3K27ac transition to safeguard ZGA by preventing premature expression of developmental genes and promoting ZGA gene activation. Our study demonstrates that coordinated activities of CBP/p300 and HDACs during mouse MZT are essential for ZGA and mouse pre-implantation development.
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Project description:How maternal factors in oocytes trigger zygotic genome activation (ZGA) is a long-standing question in developmental biology. Recent studies in 2-cell like embryonic stem cells (2C-like cells) implicate that the DUX family transcription factors are key regulators of ZGA in placental mammals. To characterize the role of DUX in ZGA, we generated Dux cluster knockout (KO) mouse lines. Unexpectedly, we found both Dux zygotic KO (Z-KO) and maternal/zygotic KO (MZ-KO) embryos can survive to adulthood despite showing reduced developmental potential. Furthermore, transcriptome profiling of the MZ-KO embryos revealed that loss of DUX has minimal effect on ZGA and most DUX targets in 2C-like cells are normally activated in MZ-KO embryos. Thus, contrary to the key function in inducing 2C-like cells, our data indicate that DUX only has a minor role in ZGA and loss of DUX is compatible with mouse development.
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Project description:Maternal-to-zygotic transition (MZT) is a conserved and fundamental process during which the maternal environment of oocyte transits to the zygotic genome driven expression program, and terminally differentiated oocyte and sperm are reprogrammed to totipotency. Metaphase II (MII) oocytes and zygotes (one-cell embryo) serve as the mature oocyte and the initiation of pre-implantation embryo development respectively, and characterizing their molecular landscapes at protein levels plays an important role in uncovering MZT and zygotic genome activation (ZGA )in mammals. Here we used an ultrasensitive proteomic approach to depict an in-depth landscape for the very early stage of mouse MZT.
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Project description:Zygotic genome activation (ZGA) is an impressed biological event following fertilization during early embryo development. Precise reprogramming of epigenetic modifications (e.g. histone H3 lysine 27 acetylation, H3K27ac) have been found contribute to safeguard ZGA in zebrafish and Drosophila, but the dynamic of H3K27ac and the underlying regulation mechanism in mammal embryos are still enigmatic yet. As the main erasers for histone acetylation, histone deacetylase 1 and 2 (HDAC1 and HDAC2) are reported essential for mouse oogenesis and embryo lineage development, while it is unclear if they are functional for ZGA. Here, we observed significant global decrease of H3K27ac during ZGA in both mouse and bovine embryos, and accumulation of HDAC1/2 is responsible for the decline of H3K27ac. Repression of HDAC1/2 by dominant negative mutation led to arrested development at late 2-cell stage in mouse embryos, accompanied by downregulation of genes supposed to be expressed during ZGA. ChIP-seq revealed abnormal distribution of H3K27ac, and DUX participates in H3K27ac aberrant hyper-acetylation in embryos overexpressed mutant HDAC1/2. Moreover, suppression of HDAC1/2 also restrains H3K4me3 removal at gene body regions via impeding expression of KDM5s during mouse ZGA, and compensatory exogenous Kdm5b mRNA can fix the exceeding H3K4me3 and failed ZGA. Intriguingly, function of HDAC1/2 seems to be conservative between mouse and bovine embryos. Together, this study reveals that HDAC1/2 is indispensable for mouse and bovine ZGA via regulating distribution of H3K27ac and H3K4me3.
2022-05-21 | GSE182554 | GEO
Project description:Zygotic genome activation (ZGA) is an impressed biological event following fertilization during early embryo development. Precise reprogramming of epigenetic modifications (e.g. histone H3 lysine 27 acetylation, H3K27ac) have been found contribute to safeguard ZGA in zebrafish and Drosophila, but the dynamic of H3K27ac and the underlying regulation mechanism in mammal embryos are still enigmatic yet. As the main erasers for histone acetylation, histone deacetylase 1 and 2 (HDAC1 and HDAC2) are reported essential for mouse oogenesis and embryo lineage development, while it is unclear if they are functional for ZGA. Here, we observed significant global decrease of H3K27ac during ZGA in both mouse and bovine embryos, and accumulation of HDAC1/2 is responsible for the decline of H3K27ac. Repression of HDAC1/2 by dominant negative mutation led to arrested development at late 2-cell stage in mouse embryos, accompanied by downregulation of genes supposed to be expressed during ZGA. ChIP-seq revealed abnormal distribution of H3K27ac, and DUX participates in H3K27ac aberrant hyper-acetylation in embryos overexpressed mutant HDAC1/2. Moreover, suppression of HDAC1/2 also restrains H3K4me3 removal at gene body regions via impeding expression of KDM5s during mouse ZGA, and compensatory exogenous Kdm5b mRNA can fix the exceeding H3K4me3 and failed ZGA. Intriguingly, function of HDAC1/2 seems to be conservative between mouse and bovine embryos. Together, this study reveals that HDAC1/2 is indispensable for mouse and bovine ZGA via regulating distribution of H3K27ac and H3K4me3.
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