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 naive and primed pluripotent stem cells and in differentiated cells, we demonstrate that JPX is a major regulator of XIST expression in human and in mouse. However, the underlying mechanisms differ radically between species and require Jpx RNA in the mouse and the act of transcription of JPX locus in the human. Moreover, biogenesis of XIST 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.