![]() ![]() X and Y chromosomes in therian mammals evolved from an ordinary pair of normally recombining autosomes 1– 3. Together, our data suggest that eutherian mammals co-opted the ancestral demethylase KDM5C during sex chromosome evolution to upregulate Xist for the female-specific induction of X-inactivation. In support, prototherian (platypus) Kdm5c also induces Xist in male mESCs. Similarly, marsupial (opossum) Kdm5c but not Kdm5d also upregulates Xist in male mESCs, despite marsupials lacking Xist, suggesting that the KDM5C function that activates Xist in eutherians is strongly conserved and predates the divergence of eutherian and metatherian mammals. Ectopic expression of mouse and human KDM5C, but not the Y-linked homolog KDM5D, induces Xist in male mouse embryonic stem cells (mESCs). Kdm5c encodes a demethylase that enhances Xist expression by converting histone H3K4me2/3 modifications into H3K4me1. Ablation of Kdm5c function in females results in a significant reduction in Xist RNA expression. 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. ![]() ![]() XX female and XY male therian mammals equalize X-linked gene expression through the mitotically-stable transcriptional inactivation of one of the two X chromosomes in female somatic cells. ![]()
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