Nature communications · 2026
XIST drives X-chromosome inactivation and safeguards female extraembryonic cells in humans.
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Panda Amitesh, Carrillo Léo, Balaton Bradley Philip, Brouillet Jeanne, Nshemereirwe Solomon, Bonroy Jarne, Alfeghaly Charbel, Facchinello Romina, Khodeer Sherif, Peredo Nicolas, Boers Ruben, Castel Gael, London Charlie, Cazottes Emmanuel, Moscatelli Madeleine, Tchinda Raissa Songwa, Pham Thi Xuan Ai, To San Kit, Allsop Ryan Nicolaas, Wang Yang, Staneva Desislava, Rugg-Gunn Peter J, Niakan Kathy K, Gribnau Joost, Ouimette Jean-François, Rougeulle Claire, Pasque Vincent
Аннотация
X-chromosome inactivation (XCI) is essential for extraembryonic tissue growth and embryo development in mice. However, species-specific differences in its timing and regulation have left its role in human development unclear. Here, we show that the in vitro differentiation of naive human pluripotent stem cells to trophoblast stem cells and extraembryonic mesoderm cells is accompanied by XCI. The inactive X chromosome displays an atypical chromatin state, lacking DNA methylation and canonical heterochromatin marks. We demonstrate that extraembryonic differentiation and XCI are temporally linked. Using loss of function approaches, we found that XIST is required for XCI establishment in humans. Furthermore, we show that XCI is needed for the survival of human female extraembryonic cells. Together, these findings link XCI to the formation of human extraembryonic lineages, with important implications for human reproductive biology.