The human inactive X chromosome modulates expression of the active X chromosome
San Roman, A.K., Godfrey, A.K., Skaletsky, H., Bellot, D.W., Groff, A.F., Bokil, N.V., Harris, H.L., Blanton, L.V., Hughes, J.F., Brown, L., Phou, S., Koutseva, N., Buscetta, A., Kruszka, P., Banks, N., Dutra, A., Pak, E., Lasutschinkow, P.C., Keen, C., Davis, S.M., Tartaglia, N.R., Samango-Sprouse, C., Muenke, M., and Page, D.C. (2023) Cell Genomics. 3(2): 100259.
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[Whitehead News: Not so inactive X chromosome]
[Whitehead News: Inactive X chromosome moves from second fiddle to the conductor’s podium]
Abstract: 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.
Graphical Abstract:
Cover Art:
X chromosome copy number varies in the human population. As reported in this issue of Cell Genomics, San Roman et al. harnessed this variation to discover that the “inactive” X chromosome regulates expression of the “active” X chromosome. The cover is inspired by Andy Warhol’s 1960s pop art paintings, which were produced contemporaneously with the discovery of X chromosome inactivation, the premier example of epigenetic regulation. As shown here, the “inactive” X chromosome can be visualized as a heterochromatic density at the nuclear periphery that is known as the “Barr body”. The cells here depict the range of X chromosome copy number interrogated in the present study – from one to four. Since all but one X chromosome is inactivated in each cell, this is visualized as zero to three Barr bodies (inactive X chromosomes). Illustration by Caitlin Rausch.
