The human inactive X chromosome modulates expression of the active X chromosome

• Published in: Cell genomics 2023-02, Vol.3 (2), p.100259, Article 100259
• Main Authors: San Roman, Adrianna K., Godfrey, Alexander K., Skaletsky, Helen, Bellott, Daniel W., Groff, Abigail F., Harris, Hannah L., Blanton, Laura V., Hughes, Jennifer F., Brown, Laura, Phou, Sidaly, Buscetta, Ashley, Kruszka, Paul, Banks, Nicole, Dutra, Amalia, Pak, Evgenia, Lasutschinkow, Patricia C., Keen, Colleen, Davis, Shanlee M., Tartaglia, Nicole R., Samango-Sprouse, Carole, Muenke, Maximilian, Page, David C.
• Format: Article
• Language: English
• Subjects: aneuploidy; dosage sensitivity; gene expression; Klinefelter syndrome; sex chromosomes; sex differences; turner syndrome; X chromosome inactivation
• ISSN: 2666-979X; 2666-979X
• DOI: 10.1016/j.xgen.2023.100259

The “inactive” X chromosome (Xi) has been assumed to have little impact, in trans, on the “active” X (Xa). To test this, we quantified Xi and Xa gene expression in individuals with one Xa and zero to three Xis. Our linear modeling revealed modular Xi and Xa transcriptomes and significant Xi-driven expression changes for 38% (162/423) of expressed X chromosome genes. By integrating allele-specific analyses, we found that modulation of Xa transcript levels by Xi contributes to many of these Xi-driven changes (≥121 genes). By incorporating metrics of evolutionary constraint, we identified 10 X chromosome genes most likely to drive sex differences in common disease and sex chromosome aneuploidy syndromes. We conclude that human X chromosomes are regulated both in cis, through Xi-wide transcriptional attenuation, and in trans, through positive or negative modulation of individual Xa genes by Xi. The sum of these cis and trans effects differs widely among genes. [Display omitted] •Analyzed gene expression in sex chromosome aneuploidy samples using linear models•Xi and Xa transcriptomes are modular•38% of X chromosome genes are affected by Xi copy number—in cis and in trans•10 X chromosome genes likely contribute to male-female differences in somatic tissues Through RNA sequencing of individuals with sex chromosome aneuploidy, San Roman et al. identify modular “active” (Xa) and “inactive” (Xi) X chromosome transcriptomes. Looking beyond classical X inactivation, which acts in cis, they find that Xi modulates Xa transcript levels in trans. They identify 10 X chromosome genes most likely to contribute to male-female differences in common disease.