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

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Alfeghaly, Charbel | Castel, Gaël | Cazottes, Emmanuel | Moscatelli, Madeleine | Moinard, Eva | Casanova, Miguel | Boni, Juliette | Mahadik, Kasturi | Lammers, Jenna | Freour, Thomas | Chauviere, Louis | Piqueras, Carla | Boers, Ruben | Boers, Joachim | Gribnau, Joost | David, Laurent | Ouimette, Jean-François | Rougeulle, Claire

Edité par CCSD ; Nature Publishing Group -

International audience. Abstract XIST (X-inactive specific transcript) long noncoding RNA (lncRNA) is responsible for X chromosome inactivation (XCI) in placental mammals, yet it accumulates on both X chromosomes in human female preimplantation embryos without triggering X chromosome silencing. The XACT (X-active coating transcript) lncRNA coaccumulates with XIST on active X chromosomes and may antagonize XIST function. Here, we used human embryonic stem 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 preimplantation development. We show that XIST triggers the deposition of polycomb-mediated repressive histone modifications and dampens the 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 before XCI, confirms the existence of a transient process of X chromosome dosage compensation and reveals that XCI and dampening rely on the same set of factors.

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