TITLE: “XIST controls X chromosome dampening and autosomal genes in early human development”
Female human pre-implantation embryos and naïve human pluripotent stem cells (hPSCs) equalize X-linked gene expression with males via X-chromosome dampening (XCD), a unique strategy of dosage compensation in mammals. The mechanisms controlling XCD are unknown. Here, we show that the long non-coding RNA XIST, which mediates X-chromosome inactivation (XCI), is required for XCD. XIST employs similar principles and protein partners, including SPEN, to execute XCD and XCI, but displays a lower accumulation and different distribution on the dampened versus the inactive X. Unexpectedly, XIST also spreads to specific autosomal regions and induces the downregulation of autosomal developmental genes in female naïve hPSCs and pre-implantation embryos. Thus, XIST balances X-linked gene expression but causes imbalances in autosomal gene expression between male and female cells in early human development. Together, our results show that the XIST-SPEN-axis can induce distinct gene expression outputs on the X-chromosome and transiently regulate autosomal genes in humans.