H3K4 methylation-promoted transcriptional memory ensures faithful zygotic genome activation and embryonic development

In the life of a vertebrate embryo, gene expression is initiated for the first time at zygotic genome activation (ZGA). Maternally expressed transcription factors present in the embryo are essential for this process. However, it is unknown if active chromatin modifications established in the gamete are propagated in the embryo as an epigenetic memory to support ZGA and embryonic development. Here, we provide evidence that in Xenopus laevis, H3K4 methylation provides an epigenetic memory of active chromatin states. We show that this is required for faithful zygotic genome activation and successful embryonic development. Chromatin configurations of promoters displaying high H3K4me3 intensity and breadth, alongside DNA hypomethylation and increased GC content, are propagated from the gametes to the embryo across multiple cell divisions and a transcriptionally quiescent phase in early development. We show that this transmission of H3K4 methylation is essential for precise zygotic genome activation and expression of key pioneer ZGA transcription factors Pou5f3.2 and Sox3. Finally, we demonstrate that the H3K4 methyltransferases Kmt2b and Cxxc1 ensure transcription-independent propagation of H3K4me3 and proper zygotic gene expression. In summary, our study establishes the role of H3K4 methylation in maintaining memory of active chromatin states in Xenopus embryos and reveals its importance for successful embryonic development.