XIST drives X-chromosome inactivation and safeguards female extraembryonic cells in humans
Abstract 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.
Authors
- Ruben Boers (ORCID: https://orcid.org/0000-0002-3377-2897)
- Emmanuel Cazottes (ORCID: https://orcid.org/0000-0002-9583-2816)
- Sherif Khodeer (ORCID: https://orcid.org/0000-0001-6851-8568)
- Amitesh Panda (ORCID: https://orcid.org/0000-0002-2702-3494)
- San Kit To (ORCID: https://orcid.org/0000-0002-3057-2902)
- Peter J. Rugg‐Gunn (ORCID: https://orcid.org/0000-0002-9601-5949)
- Bradley Philip Balaton (ORCID: https://orcid.org/0000-0002-5130-7868)
- Ryan Allsop (ORCID: https://orcid.org/0000-0002-6083-9612)
- Madeleine Moscatelli
- Nicolas Peredo (ORCID: https://orcid.org/0000-0002-4670-3700)
- Thi Xuan Ai Pham (ORCID: https://orcid.org/0000-0003-3866-2002)
- Desislava P. Staneva (ORCID: https://orcid.org/0000-0003-1330-2158)
- Gaël Castel (ORCID: https://orcid.org/0000-0002-7563-1179)
- Charbel Alfeghaly (ORCID: https://orcid.org/0000-0002-3189-900X)
- Vincent Pasque (ORCID: https://orcid.org/0000-0002-5129-0146)
- Jean‐François Ouimette (ORCID: https://orcid.org/0000-0002-4191-6336)
- Yang Wang (ORCID: https://orcid.org/0000-0003-2802-5392)
- Claire Rougeulle (ORCID: https://orcid.org/0000-0003-3861-4940)
- Raissa Songwa Tchinda
- Kathy K. Niakan (ORCID: https://orcid.org/0000-0003-1646-4734)
- Joost H. Gribnau (ORCID: https://orcid.org/0000-0001-5645-4691)
- J.P. Brouillet
- Jarne Bonroy (ORCID: https://orcid.org/0009-0004-7912-2445)
- Solomon Nshemereirwe
- Romina Facchinello
- Léo Carrillo
- Charlie London
Publication Details
- Journal
- Nature Communications
- Published
- 2026-10-22
- DOI
- https://doi.org/10.1038/s41467-026-78394-z
- Primary Topic
- Genetic and Clinical Aspects of Sex Determination and Chromosomal Abnormalities
- Type
- article
- Field-Weighted Citation Impact
- 0.00