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.
Related
- A three-factor model can explain symmetry breaking and the n-1 rule during X-chromosome inactivation
- Phase Separation Potential of Marsupial RSX RNA Reveals Convergent Evolution of X-Chromosome Inactivation Mechanisms
- A Novel NKAP Gene Frameshift Mutation in a Sardinian Family Causes Early Cell Death and Secondary Skewed X-Chromosome Inactivation and Associates with Multiple Male Miscarriages
- Lineage-specific X chromosome inactivation escape and skew underlie sex-biased immune gene dosage and deleterious variant exposure
- Cell-type-resolved DNA methylation profiling in the cortex reveals female-specific X chromosome differences in autism
BibTeX
@article{panda2026xist,
title = {{XIST drives X-chromosome inactivation and safeguards female extraembryonic cells in humans}},
author = {Amitesh Panda and Léo Carrillo and Bradley Philip Balaton and Jeanne Brouillet and Solomon Nshemereirwe and Jarne Bonroy and Charbel Alfeghaly and Romina Facchinello and Sherif Khodeer and Nicolas Peredo and Ruben Boers and Gael Castel and Charlie London and Emmanuel Cazottes and Madeleine Moscatelli and Raissa Songwa Tchinda and Thi Xuan Ai Pham and San Kit To and Ryan Nicolaas Allsop and Yang Wang and Desislava Staneva and Peter J. Rugg-Gunn and Kathy K. Niakan and Joost Gribnau and Jean-François Ouimette and Claire Rougeulle and Vincent Pasque},
journal = {Nature Communications},
year = {2026},
month = oct,
doi = {10.1038/s41467-026-78394-z},
url = {https://www.nature.com/articles/s41467-026-78394-z},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - XIST drives X-chromosome inactivation and safeguards female extraembryonic cells in humans
AU - Amitesh Panda
AU - Léo Carrillo
AU - Bradley Philip Balaton
AU - Jeanne Brouillet
AU - Solomon Nshemereirwe
AU - Jarne Bonroy
AU - Charbel Alfeghaly
AU - Romina Facchinello
AU - Sherif Khodeer
AU - Nicolas Peredo
AU - Ruben Boers
AU - Gael Castel
AU - Charlie London
AU - Emmanuel Cazottes
AU - Madeleine Moscatelli
AU - Raissa Songwa Tchinda
AU - Thi Xuan Ai Pham
AU - San Kit To
AU - Ryan Nicolaas Allsop
AU - Yang Wang
AU - Desislava Staneva
AU - Peter J. Rugg-Gunn
AU - Kathy K. Niakan
AU - Joost Gribnau
AU - Jean-François Ouimette
AU - Claire Rougeulle
AU - Vincent Pasque
PY - 2026
DA - 2026/10/22
JO - Nature Communications
DO - 10.1038/s41467-026-78394-z
UR - https://www.nature.com/articles/s41467-026-78394-z
AB - 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.
SN - 2041-1723
ER -