HCFC1 and YY1 mediate recruitment of COMPASS and Integrator to initiate X chromosome inactivation.

Boeren, J.; Tan, B.; Merzouk, S.; Rentmeester, E.; van Haperen, R.; Luchsinger Morcelle, S. J.; Maduro, C.; Rietdijk, R.; Goynuk, B.; van IJcken, W.; Demmers, J.; Gontan, C.; Mira-Bontenbal, H.; Gribnau, J.

doi:10.1101/2025.09.18.677040

bioRxiv · 10.1101/2025.09.18.677040

HCFC1 and YY1 mediate recruitment of COMPASS and Integrator to initiate X chromosome inactivation.

Boeren, J.·Tan, B.·Merzouk, S.·Rentmeester, E.·van Haperen, R.·Luchsinger Morcelle, S. J.·Maduro, C.·Rietdijk, R.·Goynuk, B.·van IJcken, W.·Demmers, J.·Gontan, C.·Mira-Bontenbal, H.·Gribnau, J.

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Abstract

The evolution of mammalian sex chromosomes has driven the emergence of mechanisms that balance X-linked gene dosage between male (XY) and female (XX) cells. In females, dosage compensation is achieved through X chromosome inactivation (XCI), initiated by upregulation of the long non-coding RNA Xist, which spreads in cis, recruiting chromatin modifiers to silence gene expression on one X chromosome. Here, we conducted a forward genetic screen and identified X-encoded Host Cell Factor 1 (HCFC1), a member of the COMPASS H3K4 methyltransferase complex, as a dose-dependent XCI-activator. HCFC1 loss results in genome-wide reduction of H3K4me3 at specific regulatory elements and downregulation of nearby genes, including Xist. We show that HCFC1 and YY1 are co-recruited genome-wide to gene regulatory elements. Mass spectrometry analysis confirmed an interaction of HCFC1 and YY1 and uncovered the Integrator complex as another prominent YY1 partner. YY1 depletion results in genome-wide loss of Integrator recruitment at gene regulatory elements and reduced expression of nearby genes, including Xist cis-regulatory genes Jpx and Ftx. These results highlight a co-regulatory role for HCFC1 in COMPASS recruitment and Xist activation, alongside YY1-mediated recruitment of Integrator to Xist regulatory elements and genes to activate female-exclusive XCI.

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Boeren, J., Tan, B., Merzouk, S., Rentmeester, E., van Haperen, R., Luchsinger Morcelle, S. J., Maduro, C., Rietdijk, R., Goynuk, B., van IJcken, W., Demmers, J., Gontan, C., Mira-Bontenbal, H., Gribnau, J.. 2025-09-18. HCFC1 and YY1 mediate recruitment of COMPASS and Integrator to initiate X chromosome inactivation.. https://doi.org/10.1101/2025.09.18.677040

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