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

Adrianna K San Roman; Alexander K Godfrey; Helen Skaletsky; Daniel W Bellott; Abigail F Groff; Hannah L Harris; Laura V Blanton; Jennifer F Hughes; Laura Brown; Sidaly Phou; Ashley Buscetta; Paul Kruszka; Nicole Banks; Amalia Dutra; Evgenia Pak; Patricia C Lasutschinkow; Colleen Keen; Shanlee M Davis; Nicole R Tartaglia; Carole Samango-Sprouse; Maximilian Muenke; David C Page

doi:10.1016/j.xgen.2023.100259

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

Cell Genom. 2023 Feb 8;3(2):100259. doi: 10.1016/j.xgen.2023.100259.

Authors

Adrianna K San Roman¹, Alexander K Godfrey^{1

2}, Helen Skaletsky^{1

3}, Daniel W Bellott¹, Abigail F Groff¹, Hannah L Harris^{1

2}, Laura V Blanton¹, Jennifer F Hughes¹, Laura Brown^{1

3}, Sidaly Phou^{1

3}, Ashley Buscetta⁴, Paul Kruszka⁴, Nicole Banks^{4

5}, Amalia Dutra⁶, Evgenia Pak⁶, Patricia C Lasutschinkow⁷, Colleen Keen⁷, Shanlee M Davis⁸, Nicole R Tartaglia^{8

9}, Carole Samango-Sprouse^{7

10

11}, Maximilian Muenke⁴, David C Page^{1

2

3}

Affiliations

¹ Whitehead Institute, Cambridge, MA 02142, USA.
² Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
³ Howard Hughes Medical Institute, Whitehead Institute, Cambridge, MA 02142, USA.
⁴ Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892, USA.
⁵ Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892, USA.
⁶ Cytogenetics and Microscopy Core, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892, USA.
⁷ Focus Foundation, Davidsonville, MD 21035, USA.
⁸ Department of Pediatrics, University of Colorado School of Medicine, Aurora, CO 80045, USA.
⁹ Developmental Pediatrics, eXtraOrdinarY Kids Program, Children's Hospital Colorado, Aurora, CO 80011, USA.
¹⁰ Department of Pediatrics, George Washington University, Washington, DC 20052, USA.
¹¹ Department of Human and Molecular Genetics, Florida International University, Miami, FL 33199, USA.

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.

Keywords: Klinefelter syndrome; X chromosome inactivation; aneuploidy; dosage sensitivity; gene expression; sex chromosomes; sex differences; turner syndrome.

Abstract

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