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Forkhead Box A2–Mediated Regulation of Female-Predominant Expression of the Mouse Cyp2b9 Gene

Department of Toxicology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama, Japan

The regulation mechanism of female-predominant expression of the mouse Cyp2b9 gene was investigated in vivo and in vitro. Luciferase reporter assay revealed that the –234/–194 region of the Cyp2b9 gene may be responsible for sexually dimorphic expression. There is a predicted forkhead box A2 (FoxA2) (hepatic nuclear factor 3β)-binding site in this region. Chromatin immunoprecipitation assay indicated that the binding protein to the site was FoxA2 in 5-week-old female mice, whereas this protein was found in both sexes at age 3 weeks, in accordance with our previous observation on the developmental expression of this gene. Mutation of the predicted FoxA2 site in the reporter construct containing the –234/+18 fragment led to complete elimination of luciferase activity, but deletion of the –234/–194 region resulted in considerable transcriptional activity, suggesting that by mutating the FoxA2-binding site a potent suppressor might bind to eliminate activity, whereas by deleting this region it could not. Sexually dimorphic secretion of growth hormone is involved in female-predominant expression of the gene, and the –234/–194 region was also responsible for suppressing the expression by male-type secretion.