Model of the epigenetic regulation of mammalian sex determination.

At the bipotential stage (E10.5), testis- (eg. Sox9) and ovary-determining (eg. Lef1) genes are bivalent, marked by both H3K27me3 and H3K4me3. Bivalent SD genes are co-expressed at low levels, poised for expression of Sry and commitment to the testis fate (XY, blue) or in absence of Sry, commitment of the ovary fate through the Wnt signaling pathway (XX, pink). Upregulation of SD genes is accompanied by loss of H3K27me3. Genes that promote the alternate fate and are repressed after sex determination (E13.5) remain bivalent. CBX2 binds to Wnt’s downstream target Lef1 in XY gonads, inhibiting its upregulation and stabilizing the testis fate. In XX E13.5 gonads, or in XY gonads that lack Cbx2, Lef1 promotes pregranulosa development which blocks upregulation of the testis fate (right, pink). It remains unclear whether CBX2 maintains H3K27me3 from the progenitor state in XY cells and is removed from specific targets in XX cells, or whether it is targeted specifically to ovary genes during Sertoli cell development.