Role of epigenetic regulation in mammalian sex determination

Mammalian sex determination is triggered by activation of the mammalian sex-determining gene, Sry, in a spatially and temporally controlled manner. Because reduced or delayed Sry expression results in male-to-female sex reversal, male development is highly dependent on the accurate transcription of Sry. SRY dysregulation is a potential cause of human disorders of sex development (DSD). In addition to changes in DNA sequences, gene expression is regulated by epigenetic mechanisms. Epigenetic regulation ensures spatial and temporal accuracy of the expression of developmentally regulated genes. Epigenetic regulation such as histone tail modification, DNA methylation, chromatin remodeling, and non-coding RNA regulation engages several biological processes in multicellular organisms. In recent years, it has been revealed that various types of epigenetic regulation are involved in accurate gonadal differentiation in mammals. In particular, histone modification plays an integral part in sex determination, which is the first step of gonadal differentiation. Here, we focus on the findings on the epigenetic modifications that regulate Sry expression. Finally, we discuss the role of metabolism that potentially alters the epigenetic state in response to environmental cues.