In mammals, after fertilization, a single egg develops into a large number (>200) of cell types through a cascade of events. During this developmental process, these cells acquire their identities through crosstalk with each other and their surrounding environment during differentiation. These interactions induce changes in patterns of gene expression that determine the fate of the cell [1]. Sex determination is a developmental process where the embryonic gonad determines the gender of an individual: male (testes) or female (ovaries) [2]. In general, there are two primary mechanisms of sex determination: environmental sex determination (ESD) and genetic sex determination (GSD). In ESD, sex is determined based on environmental conditions (temperature, salinity, density, pH, and social interactions), viz., some fish [3,4,100], reptiles [[5], [6], [7]], and amphibians [6], where sex determination occurs by temperature (TSD). While in GSD, differences at the gene level play a key role in sex differentiation, viz., mammals, several insects, etc. [8].

Although the process of selection between the two sexes is an outcome of the crosstalk of multiple mechanisms, epigenetic regulation, i.e., the inheritance of gene expression that does not require changes in nucleotide sequences, has now emerged as a significant player in this process of fate commitment [9], such as germline imprinting and X-chromosome inactivation in mammals, mating type silencing in yeast, position-effect variegation in insects, and temperature-dependent vernalization in plants [1,10]. Thus, it is easy to understand that the epigenotype, i.e., accumulation of epigenetic features in an individual cell type among multiple cell types, present in a mammalian body is different, while their genotypes are the same [11]. Methylation of DNA sequences, covalent histone modifications, non-coding RNA (ncRNAs)-mediated gene silencing, and chromatin transformation are considered representative epigenetic events [1], and these mechanisms of regulation are interdependent [11]. Several autosomal and sex-linked genes are reported to play a critical role in the alteration of chromatin 3D structure employing various epigenetic mechanisms [138]. Interestingly, a few of them are emerging as novel modifiers in sex determination (Table 1, Table 2).

Recent years have witnessed the rapid development of tools in mouse genetics for providing a better understanding of fundamental mechanisms in mammalian sex determination, gonad development, and organogenesis [12]. Several genetically modified mouse models have highlighted the molecular pathways involved in cell fate specifications during gonadogenesis, clarifying how a zygote decides its fate for testis or ovary development by utilizing mutually antagonistic regulatory networks between testis and ovary-promoting genes. However, the epigenetic mechanisms regulating the fate of developing gonads at the genome level still require further investigation. A recent study suggested that CBX2-mediated repression of ovary-determining genes is needed for stabilization of testis fate, failing which the testis pathway could be blocked [81]. The present review discusses the current knowledge about the finely tuned epigenetic regulatory mechanisms of mammalian sex determination. Furthermore, we clarify how sexually biased brain differentiation occurs before gonadogenesis and put forth a theory by highlighting the idea that sex differentiation from a sex-biased brain initiates gonadogenesis.