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

The inactiveX chromosome (Xi) has been assumed to have little impact, in trans, on the activeX (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 (R121 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.

Automated summary

The study reveals that the regulation of human X chromosomes involves both cis and trans effects, with some genes being affected by the overall Xi-wide transcriptional attenuation and others being modulated by Xi at the individual Xa gene level. These regulations play an important role in the expression changes of X chromosome genes.