The Model of the Conserved Epigenetic Regulation of Sex

Abstract

Epigenetics integrates genomic and environmental information to produce a given phenotype. Here, the model of Conserved Epigenetic Regulation of Sex (CERS) is discussed. This model is based on our knowledge on genes involved in sexual development and on epigenetic regulation of gene expression activation and silencing. This model was recently postulated to be applied to the sexual development of fish, and it states that epigenetic and gene expression patterns are more associated with the development of a particular gonadal phenotype, e.g., testis differentiation, rather than with the intrinsic or extrinsic causes that lead to the development of this phenotype. This requires the existence of genes with different epigenetic modifications, for example, changes in DNA methylation levels associated with the development of a particular sex. Focusing on DNA methylation, the identification of CpGs, the methylation of which is linked to sex, constitutes the basis for the identification of Essential Epigenetic Marks (EEM). EEMs are defined as the number and identity of informative epigenetic marks that are strictly necessary, albeit perhaps not sufficient, to bring about a specific, measurable, phenotype of interest. Here, we provide a summary of the genes where DNA methylation has been investigated so far, focusing on fish. We found that cyp19a1a and dmrt1, two key genes for ovary and testis development, respectively, consistently show an inverse relationship between their DNA methylation and expression levels, thus following CERS predictions. However, in foxl2a, a pro-female gene, and amh, a pro-male gene, such relationship is not clear. The available data of other genes related to sexual development such as sox9, gsdf, and amhr2 are also discussed. Next, we discuss the use of CERS to make testable predictions of how sex is epigenetically regulated and to better understand sexual development, as well as the use of EEMs as tools for the diagnosis and prognosis of sex. We argue that CERS can aid in focusing research on the epigenetic regulation of sexual development not only in fish but also in vertebrates in general, particularly in reptiles with temperature sex-determination, and can be the basis for possible practical applications including sex control in aquaculture and also in conservation biology.

Immune genes, IL1β and Casp9, show sexual dimorphic methylation patterns in zebrafish gonads

“…Since then, other studies, including this fish species (Anastasiadi et al, 2017;Anastasiadi et al, 2018b) have evidenced the important role of epigenetic mechanisms in the gonads. This is the case, for example, in half-smooth tongue sole, Cynoglossus semilaevis (Shao et al, 2014), Nile tilapia, Oreochromis niloticus, (Wang et al, 2017) or barramundi, Lates calcarifer (Domingos et al, 2018), among others (reviewed in Piferrer et al (2019) all of them revealing the importance of the methylation processes in reproduction-related genes in the ovaries or in the testes and thereby underlining sexual dimorphic epigenetic patterns.…”

“…Thus, in humans, for example, transcriptomic sex-related differences are more remarkable in the gonads, although they also exist in other tissues such as the brain, muscle or liver (Mele et al, 2015). In fish, transcriptomic studies identifying both the number of expressed genes between ovaries and testes and the interactions of sex-specific pathways have been carried out in several species such as zebrafish (Small et al, 2009), turbot (Ribas et al, 2016), guppy, Poecilia reticulata (Sharma et al, 2014) or E. sea bass (Ribas et al, 2019).…”

Effects of global warming on sex ratios in fishes

“…Epigenetics can be defined as “… the study of phenomena and mechanisms that cause chromosome‐bound, heritable changes to gene expression that are not dependent on changes in DNA sequence” (Deans & Maggert, 2015). With regard to temperature‐induced masculinization of gonochoristic species, most of our knowledge of epigenetics is from studies analysing methylation of promoter regions of various key sex differentiation genes (see Piferrer et al ., 2019; Ortega‐Recalde et al ., 2020 for review). A common mechanism appears to be conserved in many species that are sensitive to temperature.…”

Assessment of Biological and Sanitary Condition of Alien Fish from a High-Mountain Lake (Cottian Alps)

“…Pavlidis et al [43] showed that temperature during very early developmental stages is a key factor for sex differentiation: Low rearing temperatures (13-15 • C) result in higher proportions of females. Furthermore, epigenetic mechanisms can work with genomic and environmental factors to modify gene activity that generates a particular phenotype and sex determination as a consequence [44].…”