H3K4 methylation-promoted transcriptional memory supports faithful zygotic genome activation and development [RNA-seq-Auxin]
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. Overall design: RNA-seq profiling of H4K4me3-depleted Xenopus laevis embryos at ZGA stages using Kdm5b-wt and H3.3-K4M mRNA mutant overexpression. Kdm5b-ci (catalytically inactive) plus H3.3-wt were overexpressed as the respective control conditions. Treatments were performed either in a developmental "window" from zygote to ZGA, or "persistently" from zygote onwards.