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H3K4 methylation-promoted transcriptional memory supports faithful zygotic genome activation and development [RNA-seq-Auxin]

ABSTRACT: Accurately established transcriptional programs are paramount for successful embryonic development. At zygotic genome activation, gene expression is initiated for the first time in the life of an embryo. Pioneer transcription factors present in the embryo are essential for this process, however, the role of active chromatin modifications is less clear. It is unknown if active chromatin modifications established in the gamete are propagated in the embryo as epigenetic memory to support zygotic genome activation and development. Here, we provide evidence that in Xenopus laevis, H3K4 methylation contributes to epigenetic memory of active chromatin states, which is required for faithful zygotic genome activation and successful embryonic development. We find that chromatin configurations of promoters displaying high H3K4me3 intensity and breadth, alongside DNA hypomethylation and increased GC content, are maintained from the gametes to the embryo across multiple cell divisions and a transcriptionally quiescent phase in early development. We show that this maintenance of H3K4 methylation is essential for precise zygotic genome activation. Finally, we demonstrate that Kmt2b and Cxxc1 facilitate transcription-independent maintenance of H3K4me3 and proper zygotic gene expression. In summary, our study establishes a role for H3K4 methylation for memory of active chromatin states in embryos and reveals its importance for successful embryonic development.

ORGANISM(S): Xenopus laevis

PROVIDER: GSE286887 | GEO | 2025/01/20

REPOSITORIES: GEO

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Project description:During the first stages of development, the fertilized germ cells rapidly transition to totipotency. Maternally deposited mRNAs encode the proteins necessary for reprogramming the transcriptionally quiescent zygotic genome during this maternal-to-zygotic transition (MZT). The transcription factor Zelda is essential for this reprogramming in the Drosophila embryo. Zelda is necessary for transcriptional activation of the zygotic genome, and the absence of Zelda leads to embryonic lethality during the MZT. Excess Zelda activity is also lethal to the embryo, demonstrating that Zelda levels must be precisely controlled during early development. Because Zelda is encoded by a maternally deposited mRNA, Zelda levels in the embryo are controlled at the level of translation. To understand how levels of this essential reprogramming factor were regulated to allow for embryonic development and zygotic genome activation, we investigated the factors that regulated translation of zelda. Brain Tumor (BRAT) is a translational regulator that was previously shown to bind to zelda mRNA in the embryo. We showed that BRAT functions to repress zelda translation, as embryos deficient for maternal BRAT activity prematurely express Zelda. We further showed that in the larval brain, BRAT similarly regulates Zelda levels and identified specific BRAT-binding sites that mediate these effects. Thus, BRAT regulates Zelda in multiple tissues. Because both too little and too much Zelda are lethal to the embryo, we hypothesized that precocious expression of this transcriptional activator might be capable of driving precocious activation of the zygotic genome, leading to embryonic lethality. To test this hypothesis, we performed single embryo RNA-seq at distinct nuclear cycles throughout zygotic genome activation (NC10, NC12, NC13, and NC14) in control and brat-mutant embryos. Our results conclusively demonstrated that in embryos lacking functional BRAT, Zelda target genes were not prematurely activated. Rather, these genes were expressed normally, but become significantly upregulated at nuclear cycle 14, when the division cycle slows. Our data support a model in which zygotic genome activation requires precise coordination between expression of reprogramming factors, such as Zelda, and the slowing of the cell cycle.

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H3K4 methylation-promoted transcriptional memory supports faithful zygotic genome activation and development [RNA-seq-Auxin]

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