Precision IVF tracks how mouse embryos switch on their genome

ROME, 5 OCTOBER 2026 —

A new study published in the journal Science Advances reveals how mouse embryos precisely coordinate gene activity during early development, challenging previous assumptions about the molecular triggers of embryonic genome activation.

The findings, led by Jasmina Al-Mousawi and Ana Boskovic, provide an unprecedented high-resolution view of this critical developmental transition in mammals.

The study addresses a significant gap in developmental biology, where data from mammalian embryos have historically been scarce compared to model systems like fruit flies and zebrafish. Mammalian embryos are difficult to access and analyze regularly over time, making it challenging to track the rapid changes that occur shortly after fertilization.

During this period, the newly formed embryo must switch from relying on molecules supplied by the mother to using its own genome, a process known as embryonic genome activation (EGA). This transition is one of the earliest and most important steps in development, yet the precise mechanisms governing it in mammals remained poorly understood until now.

To overcome these technical hurdles, researchers in Ana Boskovic’s group at EMBL Rome developed a precision in vitro fertilization (IVF) protocol in mice. This technique allowed the team to precisely control when fertilization occurred, enabling them to analyze gene activity in individual embryos at several specific time points during early development. By following the embryos over a nine-hour period, the team obtained a detailed map of the gradual gene expression changes that occur during EGA.

The study highlights that even embryos that appear identical can contain vastly different RNA landscapes, depending on slight differences in their developmental timing relative to fertilization.

The data revealed extensive changes in gene activity as the embryo’s own genome became increasingly active. Concurrently, RNA inherited from the mother was gradually depleted. This switch from maternal provisions to embryonically derived molecules was marked by an increase in the activation of genes involved in essential processes such as RNA production, protein synthesis, and ribosome construction.

At the same time, the early embryo underwent widespread changes to its epigenome, the system that controls which genes are switched on or off and modulates their expression levels. These epigenetic changes included resetting chemical tags on proteins called histones, as well as removing and rebuilding DNA methylation patterns, all contributing to gene regulation during EGA.

A central focus of the research was a specific chemical modification of histone proteins called H3K4me3. Previous research had suggested that the inheritance of specific patterns of this modification from the mother might contribute to keeping genes off. Jasmina Al-Mousawi, a former Ph.D.

student in the Boskovic group and lead author of the publication, stated, "We were therefore interested in whether these processes are causally linked." Using the precision-IVF approach, the team observed that this modification is removed at the same time as the genome is activated.

To test if this removal was the cause of activation, the researchers increased the activity of an enzyme that removes H3K4me3 from histones, causing the modification to be removed earlier than it normally would be.

Surprisingly, the early removal of H3K4me3 had only a modest effect on gene activity and did not cause the embryonic genome to switch on earlier. The embryos with H3K4me3 removed continued through embryonic genome activation and developed into blastocysts at rates comparable to control embryos. These observations imply that the presence of this specific histone modification on the genome is not the molecular feature keeping the genome silent.

Al-Mousawi noted, "Previous research had suggested that the inheritance of specific patterns of this modification from the mother might contribute to keeping genes off. Using our precision-IVF approach, we could see that this modification is removed at the same time as the genome is activated."

Ana Boskovic emphasized the resilience of the early embryo in the face of such perturbations. She said, "One of the most important findings is how resilient to perturbations the early embryo appears to be.

Even when an abundant chromatin modification was removed prematurely, the embryos were still able to progress through this critical developmental transition without major adverse outcomes." The detailed dataset emerging from this study provides a useful framework for understanding the earliest stages of mammalian development and for investigating how changes in the embryonic epigenome influence development and, ultimately, phenotype.

The study also shows how flexible gene regulation is in early embryos and could inspire and enable researchers to precisely assess the quantitative impact of different perturbations on the process of genome activation. Together, the findings point toward a more complex picture of the earliest moments of embryonic development, in which the genome is switched on through a coordinated and flexible process rather than by a single molecular trigger.

The research, titled "High-resolution mapping of embryonic genome activation unveils a decoupling of transcription activation from precocious H3K4me3 removal," was published in Science Advances in 2026, with the DOI 10.1126/sciadv.aec9545.