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Illustration of H2A.Z dynamics in 5-day GOs and FGOs, and histone modification changes in H2A.Z-DKO and Mll2-KO FGOs. Credit:Nature Structural & Molecular Biology(2025). DOI: 10.1038/s41594-025-01573-x

An epigenetic factor that is essential for producing mature egg cells in mice has been identified by RIKEN researchers for the first time. This discovery could aid research into cases of infertility caused by immature eggs.

Oocytes are special cells in female mammals that go on to develop into eggs. That development involves a long and complex journey that commences before the birth of the mother and culminates in the reproductive stage later in the mother's life.

Females are born with a full set of oocytes in their ovaries, but they exist in a state of "suspended animation" in which meiosis—the special form ofcell divisionthat sperm and egg cells undergo—has been put on hold.

At puberty, oocytes grow larger by taking onboard proteins from the female. Importantly, they also receive genetic material in the form of RNA andepigenetic information—chemical tags that can regulate genes by turning them on and off. Finally, during eachmenstrual cycle, several grown oocytes end the suspended animation and resume meiosis, or cell division, to form eggs.

Oocyte development is crucial for the production of a healthy embryo. Any problems that arise in the process can jeopardize fertilization or embryo development.

A key way that epigenetic information from the female is transferred to an oocyte is via the histones—the spools around which strands of DNA are wound. The fourhistone proteins–H3, H4, H2A and H2B–each have alternative forms with slightly different chemical structures from the usual form. These histone modifications convey epigenetic information.

"Histone modifications are important for regulating genes in embryos," says Azusa Inoue of the RIKEN Center for Integrative Medical Sciences. "There are manyhistone modifications, some of which activate genes, and others that repress them."

However, scientists didn't know where H2A protein variants were located in the genome, nor their activity during oocyte development. To find out, Inoue and his team have mapped the distribution of H2A variants in fully grown oocytes of mice for the first time. Their findings arepublishedinNature Structural & Molecular Biology.

They discovered that an H2A variant known as H2A.Z, which has a slightly different amino acid sequence from H2A, is distributed in stretches of DNA located between genes. Furthermore, depletion of H2A.Z caused a drop in a H3 modification, known as H3K4me3. Conversely, reducing H3K4me3 reduces H2A.Z. In both cases,oocytedevelopment was severely impaired.

These results could be important for understanding human fertility. "We have found that H2A.Z is vital for the development of healthyoocytesin mice," says Inoue. "It's possible that defective H2A.Z could underlie some forms of infertility in people."

More information: Hailiang Mei et al, H2A.Z reinforces maternal H3K4me3 formation and is essential for meiotic progression in mouse oocytes, Nature Structural & Molecular Biology (2025). DOI: 10.1038/s41594-025-01573-x Journal information: Nature Structural & Molecular Biology

Provided by RIKEN