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bioRxiv · 10.1101/175174

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

Gayen, S.·Maclary, E.·Murata-Nakamura, Y.·Vallianatos, C. N.·Porter, R. S.·Garay, P. M.·Iwase, S.·Kalantry, S.
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Abstract

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.

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Gayen, S., Maclary, E., Murata-Nakamura, Y., Vallianatos, C. N., Porter, R. S., Garay, P. M., Iwase, S., Kalantry, S.. 2017-08-11. Induction of X-chromosome Inactivation by the Histone Demethylase SMCX/KDM5C. https://doi.org/10.1101/175174

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