ESPE Yearbook of Paediatric Endocrinology

Brief summary: This in vivo study identifies a new gene, CDYL (Chromodomain Y-like protein) in the epigenetic control of sex determination in mice.

Recent findings on mammalian sex development suggest that the fate decision of bipotential gonads depends not only on transcriptional activation of Y-linked testis-determining gene (SRY/Sry) but also on a delicate expression balance between the mutually antagonistic pro-testis and pro-ovarian genes. Particularly, epigenetic regulatory genes which are involved in the covalent modifications of DNA and histones in chromatin at the SRY locus emerged to reinforce or repress these pathways.

CDYL is a reader protein for repressive histone H3 methylation marks at the SRY locus. To test the role of CDYL in sex determination Okashita N, et al. introduced a mutant heterozygous allele of the Cdyl gene by CRISP-R Cas9 method into an Jmjd1a^Δ/Δ XY sex reversal mice model which has ovotestis containing both SOX9+ cells and FOXL2+ cells. They found that Cdyl heterozygous mutation further enhanced the XY sex reversal phenotype of Jmjd1a-deficient mice. Importantly, Cdyl mutation led to a remarkable increase in the ratio of FOXL2+ cells in the gonads of XY Jmjd1a^Δ/Δ mice. They also demonstrated XY sex reversal in a subpopulation of XY Cdyl^Δ/Δ mice in the Jmjda wild-type background. These transgenic mice showed increased Wnt4 expression and decreased Sox9 expression in the gonadal somatic cells.

By mechanism, this study demonstrated that Cdyl deficiency leads to the failure of H3K27 methylation at the Wnt4 promoter, which induces pro-ovarian Wnt4 derepression and subsequent pro-testis Sox9 repression. This suggests that Cdyl represses Wnt4 transcription through tethering H3K27 methyltransferase to its promoter as a mechanism promoting male sex determination and repressing ovarian development, independent of Sry.

Overall, these data provide further insights into the epigenetic modification of sexual differentiation.