Activation of Xist by an evolutionarily conserved function of KDM5C demethylase

Abstract

AbstractXXfemale andXYmale therian mammals equalize X-linked gene expression through the mitotically-stable transcriptional inactivation of one of the two X chromosomes in female somatic cells. Here, we describe an essential function of the X-linked homolog of an ancestral X-Y gene pair,Kdm5c-Kdm5d, in the expression of Xist lncRNA, which is required for stable X-inactivation. Ablation ofKdm5cfunction in females results in a significant reduction in Xist RNA expression.Kdm5cencodes a demethylase that enhancesXistexpression by converting histone H3K4me2/3 modifications into H3K4me1. Ectopic expression of mouse and humanKDM5C, but not the Y-linked homologKDM5D, inducesXistin male mouse embryonic stem cells (mESCs). Similarly, marsupial (opossum)Kdm5cbut notKdm5dalso upregulatesXistin male mESCs, despite marsupials lackingXist, suggesting that the KDM5C function that activatesXistin eutherians is strongly conserved and predates the divergence of eutherian and metatherian mammals. In support, prototherian (platypus)Kdm5calso inducesXistin male mESCs. Together, our data suggest that eutherian mammals co-opted the ancestral demethylase KDM5C during sex chromosome evolution to upregulateXistfor the female-specific induction of X-inactivation.