Histone Demethylation Activity of UTX Contributes to the Regulation of Steroid Biosynthesis Genes in Embryonic Gonads but Is Dispensable for Gonadal Sex Determination

Abstract

Mammalian sex is determined by the presence or absence of a Y chromosome. The sex-specific features of each cell and tissue in the body then develop in response to the sex hormones secreted by the differentiated reproductive tissues. Both the X and Y chromosomes encode histone demethylases. However, the involvement of these histone demethylases in the development of sex differences in each cell is still unknown. One X-linked demethylase, UTX, is also predicted to have both demethylase-dependent and -independent functions. In this study, we generated UTX mutant mice in which the histone demethylase activity of UTX was decreased to disrupt only the demethylase-dependent but not the demethylase-independent function of UTX. Although UTX mutant mice are viable, fertile, and never displayed sex reversal, the expression levels of sex differentiation genes were affected. Transcriptomic analyses revealed that there was a female expression pattern bias in UTX mutant males. Moreover, the steroid biosynthesis pathway was highly affected by the UTX mutation in males, with a significant decrease in the expression of the majority of steroidogenic genes. These results suggest that the demethylation activity of UTX could contribute to the development of sex differences by the regulation of steroid biosynthesis. Further analyses using the UTX mutant mice generated in this study will provide useful information to understand how sex differences develop.