Species-specific regulation of XIST by the JPX/FTX orthologs

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 (LRGs) 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 pluripotent stem- and differentiated cells, we demonstrate that the function of Ftx is not conserved, while JPX stands 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 the JPX locus in the human. Moreover, biogenesis of XIST is affected at different regulatory steps between these species. This study illustrates how diversification of LRG modus operanti during evolution provide opportunities for innovations within constrained gene regulatory networks. Two technical replicates of capture HiC sequencing from H9 human Embryonic Stem Cells