The Lid/KDM5 histone demethylase complex activates a critical effector of the oocyte-to-zygote transition

Author summary Nuclear enzymes that add or remove epigenetic marks on histone tails potentially control gene expression by affecting chromatin structure and DNA accessibility. For instance, members of the KDM5 family of histone demethylases specifically remove methyl groups on the lysine 4 of histone H3, a mark generally correlated with gene expression. Lid (Little imaginal discs), the Drosophila KDM5, is essential for viability but is also required for female fertility. In this paper, we have found that the specific removal of Lid in developing oocytes perturbs the decompaction of the sperm nucleus at fertilization and the integration of paternal chromosomes in the zygote. Sperm nuclear decompaction normally requires the presence of a small redox protein called Deadhead (Dhd), which is massively expressed at the end of oogenesis. Strikingly, our analyses of ovarian transcriptomes revealed that the absence of Lid completely abolishes the expression of dhd. This direct functional link between a general histone modifier and the expression of an essential terminal effector gene represents a rare finding. We hope that our work will help understanding how histone demethylases function in controlling complex developmental transitions as well as cancer progression. Following fertilization of a mature oocyte, the formation of a diploid zygote involves a series of coordinated cellular events that ends with the first embryonic mitosis. In animals, this complex developmental transition is almost entirely controlled by maternal gene products. How such a crucial transcriptional program is established during oogenesis remains poorly understood. Here, we have performed an shRNA-based genetic screen in Drosophila to identify genes required to form a diploid zygote. We found that the Lid/KDM5 histone demethylase and its partner, the Sin3A-HDAC1 deacetylase complex, are necessary for sperm nuclear decompaction and karyogamy. Surprisingly, transcriptomic analyses revealed that these histone modifiers are required for the massive transcriptional activation of deadhead (dhd), which encodes a maternal thioredoxin involved in sperm chromatin remodeling. Unexpectedly, while lid knock-down tends to slightly favor the accumulation of its target, H3K4me3, on the genome, this mark was lost at the dhd locus. We propose that Lid/KDM5 and Sin3A cooperate to establish a local chromatin environment facilitating the unusually high expression of dhd, a key effector of the oocyte-to-zygote transition.