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. X-chromosome inactivation (XCI) silences one of the two X chromosomes in females, but its role in human development is unclear. Here, the authors show that human extraembryonic differentiation triggers XIST-dependent XCI, important for cell survival.