XIST dampens X chromosome activity in a SPEN-dependent manner during early human development

Alfeghaly, C.; Castel, G.; Cazottes, E.; Moscatelli, M.; Moinard, E.; Casanova, M.; Boni, J.; Mahadik, K.; Lammers, J.; Freour, T.; Chauviere, L.; Piqueras, C.; Boers, R.; Boers, J.; Gribnau, J.; David, L.; Ouimette, J.-F.; Rougeulle, C.

doi:10.1101/2023.10.19.563078

bioRxiv · 10.1101/2023.10.19.563078

XIST dampens X chromosome activity in a SPEN-dependent manner during early human development

Alfeghaly, C.·Castel, G.·Cazottes, E.·Moscatelli, M.·Moinard, E.·Casanova, M.·Boni, J.·Mahadik, K.·Lammers, J.·Freour, T.·Chauviere, L.·Piqueras, C.·Boers, R.·Boers, J.·Gribnau, J.·David, L.·Ouimette, J.-F.·Rougeulle, C.

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Abstract

XIST long non-coding RNA is responsible for X chromosome inactivation (XCI) in placental mammals, yet it accumulates on both X chromosomes in human female pre-implantation embryos without triggering X chromosome silencing. The long non-coding RNA XACT co-accumulates with XIST on active Xs and may antagonize XIST function. Here we used human ES cells in a naive state of pluripotency to assess the function of XIST and XACT in shaping the X chromosome chromatin and transcriptional landscapes during pre-implantation development. We show that XIST triggers the deposition of polycomb-mediated repressive histone modifications and attenuates transcription of most X-linked genes in a SPEN-dependent manner, while XACT deficiency does not significantly affect XIST activity or X-linked gene expression. Our study demonstrates that XIST is functional prior to XCI, confirms the existence of a transient process of X chromosome dosage compensation, and reveals that X chromosome inactivation and dampening rely on the same set of factors.

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Alfeghaly, C., Castel, G., Cazottes, E., Moscatelli, M., Moinard, E., Casanova, M., Boni, J., Mahadik, K., Lammers, J., Freour, T., Chauviere, L., Piqueras, C., Boers, R., Boers, J., Gribnau, J., David, L., Ouimette, J.-F., Rougeulle, C.. 2023-10-19. XIST dampens X chromosome activity in a SPEN-dependent manner during early human development. https://doi.org/10.1101/2023.10.19.563078

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