Azusa Inoue

New research from IMS addresses a fundamental question in developmental biology: how maternal epigenetic information is established in oocytes and reveals the consequences of failures in this process.

Epigenetic modifications, especially posttranslational modifications of histones, are crucial regulators of all aspects of development and differentiation. In mammals, the production of developmentally competent oocytes is essential for embryo development. Primordial oocytes are generated before birth and undergo meiotic arrest in the ovaries for months to years, depending on the species, until puberty. They then grow in size without cell cycle progression, accumulating maternal proteins, RNA, and epigenetic information, all of which are important for subsequent meiotic progression and normal development after fertilization. The focus of Dr. Inoue and his colleagues here is on the unique landscape of histone modifications in oocytes, some of which are inherited by early embryos, since it is unknown how histone variants shape the maternal histone landscape.

By way of background, histones are classified as canonical and non-canonical. The former package DNA into nucleosomes and are DNA replication-dependent and expressed in S-phase. Their modifications at defined sites include acetylation, methylation, ubiquitination, etc. Non-canonical (nc) variant histones, e.g., H2A.Z, H2A.X, macro H2A, TH2A, and H3.3, are replication-independent and can be expressed throughout the cell cycle. They may be transiently deposited or evicted from chromatin, thus providing a flexible mechanism of gene regulation. Here, the authors mapped the distribution of H2A variants and canonical H2A in fully grown oocytes (FGO) of mice and found that H2A.Z forms broad domains across intergenic regions, coinciding with another histone mark, ncH3K4me3. In functional studies, they showed that depletion of H2A.Z in oocytes partially impaired intergenic ncH3K4me3 formation and caused severe defects in meiotic progression. This phenotype resembles that seen in Mll2-knockout oocytes, which lack the H3K4me3 modification. The Mll2 knockout also caused a reduction of intergenic ncH2A.Z in FGOs. These studies have revealed an unprecedented epistasis between ncH2A.Z and ncH3K4me3 across intergenic regions and their phenotypic similarities.

Original Paper

Mei, H., Hayashi, R., Kozuka, C., Kumon, M., Koseki, H. & Inoue, A. H2A.Z reinforces maternal H3K4me3 formation and is essential for meiotic progression in mouse oocytes. Nat Struct Mol Biol 32, 1883–1893 (2025). doi: 10.1038/s41594-025-01573-x

https://www.nature.com/articles/s41594-025-01573-x