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

Abstract

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.

The emerging role of transcriptional regulation in the oocyte-to-zygote transition

“…dhd encodes a thioredoxin-like protein that was previously described to be essential for sperm chromatin decompaction after fertilization [17]. The authors observed that dhd expression was severely reduced in Kdm5-depleted oocytes [5], which is in accordance with their recorded incapability of forming the paternal pronucleus. Importantly, Kdm5 depletion was associated with a sharp decrease of H3K4me3 across the dhd gene body, suggesting that Kdm5 directly regulates dhd expression.…”

“…Not surprisingly, the loss of Kdm5 and its demethylase activity are associated with a significant reduction of female fertility [15]. Now Torres-Campana and colleagues [5] further expand the gamut of Kdm5-related functions during oogenesis to include the transcriptional regulation of deadhead (dhd)-a major player in the oocyte-to-zygote transition. dhd encodes a thioredoxin-like protein that was previously described to be essential for sperm chromatin decompaction after fertilization [17].…”

“…An important point from Torres-Campana and colleagues' study [5] regards the experiment in which the authors attempt to suppress, via ectopic expression of dhd, the sperm chromatin-remodeling defects of Kdm5-depleted oocytes. The outcome of this experiment was a quite modest degree of functional rescue, which clearly suggests that besides dhd, Kdm5 regulates the expression of other genes similarly important for postfertilization development.…”

Identification of New Regulators of the Oocyte-to-Embryo Transition inDrosophila

“…We reasoned that changes in protein levels could be diagnostic of proteins with pivotal roles during the events of oocyte maturation and egg activation in Drosophila. Indeed, many known key regulators, such as GNU, LID and DHD, exhibit protein level patterns that are consistent with their functions during the transition ( Torres-Campana et al 2020 ; Kronja et al 2014a ; Petrova et al 2018 ). Similar to these proteins, many other proteins show protein level patterns suggestive of developmental control ( Kronja et al 2014a ).…”

Structures of the germline-specific Deadhead and Thioredoxin T proteins fromDrosophila melanogasterreveal unique features among Thioredoxins

“…Moreover, Dhd plays crucial roles in the oocyte-to-embryo transition, where it reduces and modulates the activity of ribosomal and RNA-binding proteins, as well as that of the histone demethylase NO66 protein (18). Recently, it has also been reported that the transcriptional regulation of Dhd is modulated by the lysine-specific demethylase 5 (KDM5), a potent chromatin remodeler during female gametogenesis (19).…”