In mammals, commitment to the testis fate is controlled by the gene Sry on the Y chromosome; however, how Sry is regulated is not well understood. In the red-eared slider turtle, Dmrt1 acts as the primary activator of the testis pathway. Removal of the repressive histone modification H3K27me3 from Dmrt1 by the histone demethylase KDM6B is required for its activation. We hypothesized that a similar de-repression mechanism is used in mammals to activate the testis pathway. Using a mouse knockout model for Kdm6b, we found that loss of Kdm6b leads to a delay in Sry activation and the development of an ovotestis. These results implicate KDM6B as a conserved regulator at the top of the sex determination cascade in both reptiles and mammals.

Keywords:
Sex determination, Epigenetics, Demethylase, Sry, Kdm6b, Histone modifications
Subjects:
Cell fate control and differentiation, Chromatin and epigenetics

Author contributions

Conceptualization: S.M.D., A.G.-M., B.C.C.; Data curation: S.M.D., A.G.-M., E.V.O., B.C.C.; Formal analysis: S.M.D., A.G.-M., E.V.O., B.C.C.; Funding acquisition: S.M.D., A.G.-M., E.V.O., B.C.C.; Investigation: S.M.D., B.C.C.; Methodology: S.M.D., A.G.-M., E.V.O., B.C.C.; Project administration: S.M.D., B.C.C.; Resources: S.M.D., A.G.-M., B.C.C.; Software: S.M.D., A.G.-M., B.C.C.; Supervision: S.M.D., B.C.C.; Validation: S.M.D., A.G.-M., B.C.C.; Visualization: S.M.D., A.G.-M., B.C.C.; Writing – original draft: S.M.D., B.C.C.; Writing – review & editing: S.M.D., A.G.-M., E.V.O., B.C.C.

Funding

S.M.D. and B.C.C. are currently supported by a grant from the National Institutes of Health (R01-HD039963 R37-HD039963 to B.C.C.). Deposited in PMC for release after 12 months.

Data and resource availability

The RNA-sequencing data generated in this study has been deposited in GEO under accession number GSE295878.

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2025
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