Mechanistic diversification of XIST regulatory network in mammals

X chromosome inactivation (XCI) is a developmental regulatory process that initiates with remarkable diversity in various mammalian species. Here we addressed the contribution of XCI regulators, most of which are lncRNA genes characterized in the mouse, to this mechanistic diversity. By combining analysis of single-cell RNA-seq data from early human embryogenesis with various functional assays in naïve and primed pluripotent stem cells and in differentiated cells, we demonstrate that is a major regulator of expression in human and in mouse. However, the underlying mechanisms differ radically between species and require RNA in the mouse and the act of transcription of locus in the human. Moreover, biogenesis of is affected at different regulatory steps between these species. This study illustrates how diversification of LRGs modes of action during evolution provide opportunities for innovations within constrained gene regulatory networks.