XIST directly regulates X-linked and autosomal genes in naïve human pluripotent cells [ChIP-seq]
X-chromosome inactivation (XCI) serves as a paradigm for RNA-mediated regulation of gene expression, wherein the long non-coding RNA XIST spreads across the X-chromosome in cis to mediate chromosome-wide gene silencing. In female naïve human pluripotent stem cells (hPSCs), XIST is in a dispersed configuration and XCI does not occur, raising questions about XIST's function. We found that XIST spreads across the X-chromosome and induces dampening of X-linked gene expression in naïve hPSCs. Surprisingly, XIST also targets specific autosomal regions, where it induces repressive chromatin changes and gene expression dampening. Thereby, XIST equalizes X-linked gene dosage between male and female cells while inducing differences on autosomes. The dispersed Xist configuration and autosomal localization also occur transiently during XCI initiation in mouse PSCs. Together, our study identifies XIST as the regulator of X-chromosome dampening, uncovers an evolutionarily conserved trans-acting role of XIST/Xist, and reveals a correlation between XIST/Xist dispersal and autosomal targeting. Surprisingly, XIST also targets specific autosomal regions, where it induces repressive chromatin changes and gene expression dampening. Thereby, XIST equalizes X-linked gene dosage between male and female cells while inducing differences on autosomes. Dispersed Xist configuration and autosomal localization also occur transiently during XCI initiation in mouse PSCs. Together, our results identify XIST as the regulator of X-chromosome dampening, uncover an evolutionarily conserved trans-acting role of XIST/Xist, and reveal a correlation between XIST/Xist dispersal and autosomal targeting. Overall design: We examined multiple histone marks in female human naive iPSCs and in male human naive hESCs (WIN1)