Figure 1: Fish embryos 34 hours after fertilization during zygotic genome activation. A RIKEN researcher and his colleague have determined the mechanism of gene expression during this stage. © 2025 RIKEN Center for Integrative Medical Sciences
A RIKEN researcher and his colleague have identified how genes are expressed in fish embryos when they first start using their own genetic material1. If the same mechanisms apply to humans, they could shed light on developmental problems.
After an egg is fertilized by a sperm, the fertilized egg initially relies on proteins and RNA it received from its mother. But after several cell divisions, it undergoes a critical transition and switches to using its own genome to guide development.
Known as zygotic genome activation (ZGA), this transition is accompanied by a flurry of genetic activity.
"Unlike normal transcription of DNA in typical cells, more than 1,000 genes are simultaneously activated in only a few hours during ZGA in non-mammalian species," explains Hiroto Fukushima of the RIKEN Center for Integrative Medical Sciences. "This implies that transcription during ZGA proceeds in a unique manner, but the regulations that govern it have yet to be identified."
One way the genome in embryos is modified during ZGA is through chemical changes to the four different proteins that make up histones-the spools around which DNA is wrapped. Such histone modifications can turn the expression of certain genes on or off. However, their roles in ZGA hadn't been fully clarified until now.
Fukushima first became interested in this question serendipitously. "While teaching an undergraduate student about an unrelated topic, I was very surprised when I found that the active histone modification H3K27ac is strongly accumulated specifically during ZGA," he recalls. "I first thought it was an artifact, but it proved to be reproducible."
Previously, the only other observation of such strong enrichment of histone modification was during sperm production. That led Fukushima to wonder whether the exceptional accumulation of H3K27ac was important for the unique nature of transcription during ZGA.
Fukushima and Hiroyuki Takeda of Kyoto Sangyo University have now comprehensively examined the roles of histone modifications in zebrafish and Japanese rice fish embryos (Fig. 1).
The pair discovered that H3K27ac and another histone modification, H3.3S31ph, activate developmental genes during ZGA by modulating RNA polymerase activity.
"The function of H3.3S31ph during ZGA is particularly significant," says Fukushima. "It's known to be involved in regulating the cell cycle, and the cycle slows dramatically after ZGA in non-mammalian species."
The researchers found that at least six histone modifications coordinate to regulate ZGA. They also discovered that developmental genes-those that play key roles in development-and housekeeping genes, which are needed for normal cellular functions, are activated by different active histone modifications.
The findings confirm the special nature of ZGA. "As we expected, our data indicates that gene activation during ZGA occurs in a unique manner," says Fukushima.
