Decoding the epigenetic mechanism of mammalian sex determination: Updates, emerging hypothesis and unsolved questions

• Published in: Experimental cell research 2024-03, p.114011
• Main Authors: Kumar, Cash, Roy, Jagat Kumar
• Format: Article
• Language: English
• ISSN: 1090-2422
• DOI: 10.1016/j.yexcr.2024.114011

Sex determination embodies a dynamic and intricate developmental process wielding significant influence over the destiny of bipotential gonads, steering them towards male or female gonads. Gonadal differentiation and the postnatal manifestation of the gonadal phenotype involve a sophisticated interplay of transcription factors such as SOX9 and FOXL2. Central to this interplay are chromatin modifiers regulating the mutual antagonism during this interplay. In this review, the key findings and knowledge gaps in DNA methylation, histone modification, and non-coding RNA-mediated control throughout mammalian gonadal development are covered. Furthermore, it explores the role of the developing brain in playing a pivotal role in the initiation of gonadogenesis and the subsequent involvement of gonadal hormones in fine-tuning sexual differentiation. Based on promising facts, the role of the developing brain through the hypothalamic pituitary gonadal axis is explained and suggested as a novel hypothesis. The article also explains the potential impact of ecological factors on the human epigenome in relation to sex determination and trans-generational epigenetics in uncovering novel genes and mechanisms involved in sex determination and gonadal differentiation. We have subtly emphasized the disruptions in epigenetic regulations contributing to sexual disorders, which further allows us to raise certain questions and approaches for handling these questions, setting up the direction of future research.