XIST regulates X-linked and autosomal genes in naive human pluripotent cells. In female naive human pluripotent stem cells (hPSCs), XIST is in a dispersed configuration and X chromosome inactivation (XCI) does not occur. However, XIST spreads across the X chromosome and induces gene expression dampening. XIST also targets specific autosomal regions, inducing repressive chromatin changes and gene expression dampening. This results in equalizing X-linked gene dosage between male and female cells while inducing differences in autosomes. XIST's dispersed configuration and autosomal localization also occur transiently during XCI initiation in mouse PSCs. The 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. XIST mediates chromatin changes at target regions on the X and autosomes, and its function is shown to be critical for XCD in female naive hPSCs. XIST also mediates the repression of autosomal genes, leading to male-biased expression. The study highlights the role of XIST in regulating gene expression and chromatin state on the X chromosome and autosomes, and shows that XIST can generate two functionally different outputs—dampening (XCD) and silencing (XCI). The findings suggest that XIST has opposing functions, equalizing X-linked while unbalancing autosomal gene expression. The study also reveals that XIST induces sexually dimorphic H3K27me3 profiles at a subset of its autosomal targets, which may carry an epigenetic memory and have a lasting impact on development. The study has limitations, including the inability to extract inter- and intra-chromosomal interactions from naive hPSCs due to the need for high-resolution contact maps. The study also notes that female naive hPSCs express XIST only from one X chromosome, unlike the embryo with two XIST-expression X chromosomes. However, the monoallelic expression of XIST in hPSCs allowed for the exploration of whether the XIST-associated chromosome is specifically regulated. The study also notes that X chromosome upregulation may occur on the XIST-negative X chromosome. Overall, the study provides important insights into the role of XIST in regulating gene expression and chromatin state in naive human pluripotent cells.XIST regulates X-linked and autosomal genes in naive human pluripotent cells. In female naive human pluripotent stem cells (hPSCs), XIST is in a dispersed configuration and X chromosome inactivation (XCI) does not occur. However, XIST spreads across the X chromosome and induces gene expression dampening. XIST also targets specific autosomal regions, inducing repressive chromatin changes and gene expression dampening. This results in equalizing X-linked gene dosage between male and female cells while inducing differences in autosomes. XIST's dispersed configuration and autosomal localization also occur transiently during XCI initiation in mouse PSCs. The 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. XIST mediates chromatin changes at target regions on the X and autosomes, and its function is shown to be critical for XCD in female naive hPSCs. XIST also mediates the repression of autosomal genes, leading to male-biased expression. The study highlights the role of XIST in regulating gene expression and chromatin state on the X chromosome and autosomes, and shows that XIST can generate two functionally different outputs—dampening (XCD) and silencing (XCI). The findings suggest that XIST has opposing functions, equalizing X-linked while unbalancing autosomal gene expression. The study also reveals that XIST induces sexually dimorphic H3K27me3 profiles at a subset of its autosomal targets, which may carry an epigenetic memory and have a lasting impact on development. The study has limitations, including the inability to extract inter- and intra-chromosomal interactions from naive hPSCs due to the need for high-resolution contact maps. The study also notes that female naive hPSCs express XIST only from one X chromosome, unlike the embryo with two XIST-expression X chromosomes. However, the monoallelic expression of XIST in hPSCs allowed for the exploration of whether the XIST-associated chromosome is specifically regulated. The study also notes that X chromosome upregulation may occur on the XIST-negative X chromosome. Overall, the study provides important insights into the role of XIST in regulating gene expression and chromatin state in naive human pluripotent cells.