Female Bias in Rhox6 and 9 Regulation by the Histone Demethylase KDM6A

The rhox cluster on the mouse x chromosome contains reproduction-related homeobox genes expressed in a sexually dimorphic manner. we report that two members of the rhox cluster,rhox6 and 9,are regulated by de-methylation of histone h3 at lysine 27 by kdm6a,a histone demethylase with female-biased expression. consistent with other homeobox genes,rhox6 and 9 are in bivalent domains prior to embryonic stem cell differentiation and thus poised for activation. in female mouse es cells,kdm6a is specifically recruited to rhox6 and 9 for gene activation,a process inhibited by kdm6a knockdown in a dose-dependent manner. in contrast,kdm6a occupancy at rhox6 and 9 is low in male es cells and knockdown has no effect on expression. in mouse ovary where rhox6 and 9 remain highly expressed,kdm6a occupancy strongly correlates with expression. our study implicates kdm6a,a gene that escapes x inactivation,in the regulation of genes important in reproduction,suggesting that kdm6a may play a role in the etiology of developmental and reproduction-related effects of x chromosome anomalies. © 2013 berletch et al.