The H3.3 chaperone Hira complex orchestrates oocyte developmental competence

Successful reproduction requires an oocyte competent to sustaining early embryo development. By the end of oogenesis, the oocyte has entered a transcriptionally silenced state, the mechanisms and significance of which remain poorly understood. Histone H3.3, an H3 variant, has unique cell cycle-independent functions in chromatin structure and gene expression. Here we characterised H3.3 chaperone Hira/Cabin1/Ubn1 complex showing that loss-of-function of any of these subunits causes early embryogenesis failure. Transcriptome and nascent RNA analyses revealed that transcription is aberrantly silenced in mutant oocytes. Histone marks including H3K4me3 and H3K9me3 are reduced and chromatin accessibility is impaired in Hira/Cabin1 mutants. Misregulated genes in mutant oocytes include Zscan4, a 2-cell specific gene involved in zygote genome activation. Overexpression of Zscan4 in the oocyte partially recapitulates the phenotypes of Hira mutants and Zscan4 knockdown in Cabin1 mutant oocytes partially restored their developmental potential, illustrating that temporal and spatial expression of Zscan4 is fine-tuned at the oocyte-to-embryo transition. Thus, the H3.3 chaperone Hira complex has a maternal effect function in oocyte developmental competence and embryogenesis by modulating chromatin condensation and transcriptional quiescence.