4D nucleome landscape reveals dissolution of bipartite active X chromosome in liver cancer development

Changes of three-dimensional chromosome organization in cancers are well established, but little focus has been placed on the behaviour of X chromosome (chrX). Here we show that hepatic chrX of male mice exhibits chromosome segregation, which is attenuated during hepatocellular carcinoma (HCC) development. Using F1 hybrid mice, we find that both conformation change and gene activation on male active chrX (Xa) are more pronounced than those on female Xa, which is correlated with male bias in liver diseases. Of note, analysis of human hepatic tissues demonstrates that normal Xa possesses a bipartite mega-domain structure, which is dissolved in fibrotic and HCC tissues across both sexes. This bipartite Xa is liver-specific, and shows little correlation with ploidy status. Furthermore, deletion of the megabase-scale Xa boundary via CRISPR-Cas3 disrupts the bipartite Xa conformation and drives a premalignant transition. Together, this comprehensive analysis highlights a key role of Xa conformation change in promoting HCC development.