XY male and XX female mammals equalize X-linked gene expression through the mitotically-stable transcriptional inactivation of an X-chromosome in females. Although most genes are silent on the inactive-X, some escape silencing and are expressed at higher levels in females vs. males. Here, we show that the escapee Smcx/Kdm5c, encoding a histone H3K4me2/3 demethylase, underlies the female-specific induction of X-inactivation. Mouse embryonic epiblast cells and differentiating embryonic stem cells (ESCs) lacking SMCX show reduced expression of Xist RNA, which is required for X-inactivation. Smcx-heterozygous epiblast cells do not silence X-linked genes efficiently, despite robust Xist expression. Overexpression of mouse or human SMCX, but not a catalytically-inactive SMCX or the Y-chromosome homolog SMCY, is sufficient to induce Xist and, separately, to silence X-linked genes in male ESCs. Finally, SMCX dose is inversely correlated with H3K4me2 at X-linked loci. Thus, X-inactivation initiates through the evolutionarily conserved, dose-dependent function of the histone demethylase SMCX.

Induction of X-chromosome Inactivation by the Histone Demethylase SMCX/KDM5C