The Chromatin State during Gonadal Sex Determination

Abstract

At embryonic day (E) 10.5, prior to gonadal sex determination, XX and XY gonads are bipotential and able to differentiate into either a testis or an ovary. At this point, they are transcriptionally and morphologically indistinguishable. Sex determination begins around E11.5 in the mouse when the supporting cell lineage commits to either Sertoli or granulosa cell fate. Testis-specific factors such as SRY and SOX9 drive differentiation of bipotential-supporting cells into the Sertoli cell pathway, whereas ovary-specific factors like WNT4 and FOXL2 guide differentiation into granulosa cells. It is known that these 2 pathways are mutually antagonistic, and repression of the alternative fate is critical for maintenance of the testis or ovary programs. While we understand much about the transcription factor networks guiding the process of sex determination, it is only more recently that we have begun to understand how this process is epigenetically controlled. Studies in the past decade have demonstrated the importance of the chromatin state for gene expression and cell fate commitment, with histone modifications and DNA accessibility having a direct role in gene regulation. It is now clear that the chromatin state during sex determination is dynamic and likely critical for the establishment and/or maintenance of the transcriptional programs. Prior to sex determination, supporting cells have similar chromatin structure and histone modification profiles, reflecting the bipotential nature of these cells. After differentiation to Sertoli or granulosa cells, the chromatin state acquires sex-specific profiles. The proteins that regulate the deposition of histone modifications or the opening of compact chromatin likely play an important role in Sertoli and granulosa cell fate commitment and gonad development. Here, we describe studies profiling the chromatin state during gonadal sex determination and one example in which depletion of <i>Cbx2</i>, a member of the Polycomb Repressive Complex 1 (PRC1), causes male-to-female sex reversal due to a failure to repress the ovarian pathway.

Pervasive male-biased expression throughout the germline-specific regions of the sea lamprey genome supports key roles in sex differentiation and spermatogenesis

“…An increasing number of studies indicate roles for both chromatin modification and changes in DNA methylation in sex determination. Proteins involved in histone modification or the opening of dense chromatin play a key role in germ cell fate and gonad development in mice 36 , 37 . On the other hand, changes in DNA methylation of the promoter region of Sry , essential for mammalian testis development, regulate the temporal expression of Sry in mice 38 .…”

Polystyrene nanoplastics aggravate reproductive system damage in obese male mice by perturbation of the testis redox homeostasis

“…Sertoli cells are the main cells that maintain the testicular BTB, and their number determines the progression of normal spermatogenesis 52,56,57 . After observing the destruction of BTB, we analyzed the expression levels of SOX9, a marker protein of Sertoli cells, 58 and results showed that both PS‐NPs and HFDs inhibited the number of Sertoli cells, and their joint effect exacerbated the inhibitory response. Sertoli cells have an important impact on spermatogenesis because they provide nutritional and immune support for spermatogenesis 59 .…”

Loss of Raptor induces Sertoli cells into an undifferentiated state in mice

“…SOX9 stimulates the expression of Pgds [ 6 ], which in turn amplifies SOX9 activity synergistically with FGF9 [ 7–9 ], further inducing differentiation of supporting cell lineages to the Sertoli cell (SC) fate and establishing the testicular cords. It has been recently demonstrated that expression of Sry is controlled by the epigenetic machinery by specific transcription factors, and epigenetic regulation plays an important role in gonadal sex determination [ 10 , 11 ]. In the absence of Sry or Sox9 activation, granulosa cell fate and ovary pathway are initiated, mainly involving the R-spondin1 (RSPO1)/WNT4-β-catenin signaling pathway [ 12–14 ], in coordination with FOXL2 [ 15–17 ] and Follistatin [ 18 ].…”