Wnt4 as a signal coordinates DNA methylation and acetylation to determine germ line fate

Florence Naillat; Shin-Ichi Tomizawa; Elena Ivanova; Gavin Kelsey; Seppo J Vainio

doi:10.1016/j.ydbio.2026.04.015

Wnt4 as a signal coordinates DNA methylation and acetylation to determine germ line fate

Dev Biol. 2026 Apr 22:535:111-123. doi: 10.1016/j.ydbio.2026.04.015. Online ahead of print.

Authors

Florence Naillat¹, Shin-Ichi Tomizawa², Elena Ivanova³, Gavin Kelsey⁴, Seppo J Vainio⁵

Affiliations

¹ Faculty of Biochemistry and Molecular Medicine, Biocenter Oulu, Oulu University, Finland; Epigenetics Program, Babraham Institute, Cambridge, UK. Electronic address: florence.naillat@oulu.fi.
² Epigenetics Program, Babraham Institute, Cambridge, UK; School of Medicine, Yokohama City University, Japan.
³ Epigenetics Program, Babraham Institute, Cambridge, UK.
⁴ Epigenetics Program, Babraham Institute, Cambridge, UK; Centre for Trophoblast Research, University of Cambridge, UK.
⁵ Faculty of Biochemistry and Molecular Medicine, Biocenter Oulu, Oulu University, Finland; Kvantum Institute, University of Oulu, Finland.

PMID: 42031195
DOI: 10.1016/j.ydbio.2026.04.015

Abstract

Wnt4 signaling promotes somatic cell development in the female embryo, but its role in germline differentiation during meiosis remains poorly characterized. To explore Wnt4 functions in female embryonic gonads, we isolated germ cells from Wnt4 knock-out mice to investigate histone modifications and DNA methylation distribution patterns. The lack of the Wnt4 signaling pathway deregulates germ cell cycle markers, such as cyclins, alters the cell cycle by impairing meiosis progression, maintains the germ cells in the G1-GO and S phases, and supporting DNMT3A and DNMT1 enzyme expression at meiosis entry. Conversely, in the nucleus of the Wnt4 knock-out female germ cells, an increase of H3K27me3 pattern persists at the entry of meiosis, leading to altered methylation at the Sycp3 promoters combined with an acetylation of Stra8 promoter at E14.5. This changed pattern might be explained by the overexpression of Creb-binding protein (CBP) in the mutant female germ cells, leading to deregulation of histone marks on meiosis genes. Our findings reveal that the Wnt4 signal is necessary for inducing meiosis by inhibiting germ cell proliferation via the regulation of histone modification. Wnt4 signaling plays a crucial role in regulating the delicate balance between DNA methylation and acetylation in female germ cells. This fascinating interaction highlights the complexities of cellular processes that contribute to reproductive health and development.

Keywords: CBP; DNA methylation; DNMT; Germ cells; H3K27Ac; H3K27me3; Meiosis; Transcription; Wnt4; p300.