CDYL reinforces male gonadal sex determination through epigenetically repressing Wnt4 transcription in mice

Proc Natl Acad Sci U S A. 2023 May 16;120(20):e2221499120. doi: 10.1073/pnas.2221499120. Epub 2023 May 8.


In mammals, male and female gonads initially develop from bipotential progenitor cells, which can differentiate into either testicular or ovarian cells. The decision to adopt a testicular or ovarian fate relies on robust genetic forces, i.e., activation of the testis-determining gene Sry, as well as a delicate balance of expression levels for pro-testis and pro-ovary factors. Recently, epigenetic regulation has been found to be a key element in activation of Sry. Nevertheless, the mechanism by which epigenetic regulation controls the expression balance of pro-testis and pro-ovary factors remains unclear. Chromodomain Y-like protein (CDYL) is a reader protein for repressive histone H3 methylation marks. We found that a subpopulation of Cdyl-deficient mice exhibited XY sex reversal. Gene expression analysis revealed that the testis-promoting gene Sox9 was downregulated in XY Cdyl-deficient gonads during the sex determination period without affecting Sry expression. Instead, we found that the ovary-promoting gene Wnt4 was derepressed in XY Cdyl-deficient gonads prior to and during the sex-determination period. Wnt4 heterozygous deficiency restored SOX9 expression in Cdyl-deficient XY gonads, indicating that derepressed Wnt4 is a cause of the repression of Sox9. We found that CDYL directly bound to the Wnt4 promoter and maintained its H3K27me3 levels during the sex-determination period. These findings indicate that CDYL reinforces male gonadal sex determination by repressing the ovary-promoting pathway in mice.

Keywords: CDYL; H3K27me3; WNT4; gonadal sex determination.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Epigenesis, Genetic*
  • Female
  • Gene Expression Regulation, Developmental
  • Gonads / metabolism
  • Male
  • Mammals / genetics
  • Mice
  • Ovary / metabolism
  • SOX9 Transcription Factor / genetics
  • SOX9 Transcription Factor / metabolism
  • Sex Determination Processes* / genetics
  • Sex-Determining Region Y Protein / genetics
  • Sex-Determining Region Y Protein / metabolism
  • Testis / metabolism
  • Wnt4 Protein / genetics
  • Wnt4 Protein / metabolism


  • Sex-Determining Region Y Protein
  • SOX9 Transcription Factor
  • Wnt4 Protein
  • Wnt4 protein, mouse
  • Cdyl protein, mouse