Cell Genomics (Feb 2023)
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
Affiliations
- Adrianna K. San Roman
- Whitehead Institute, Cambridge, MA 02142, USA
- Alexander K. Godfrey
- Whitehead Institute, Cambridge, MA 02142, USA; Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA
- Helen Skaletsky
- Whitehead Institute, Cambridge, MA 02142, USA; Howard Hughes Medical Institute, Whitehead Institute, Cambridge, MA 02142, USA
- Daniel W. Bellott
- Whitehead Institute, Cambridge, MA 02142, USA
- Abigail F. Groff
- Whitehead Institute, Cambridge, MA 02142, USA
- Hannah L. Harris
- Whitehead Institute, Cambridge, MA 02142, USA; Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA
- Laura V. Blanton
- Whitehead Institute, Cambridge, MA 02142, USA
- Jennifer F. Hughes
- Whitehead Institute, Cambridge, MA 02142, USA
- Laura Brown
- Whitehead Institute, Cambridge, MA 02142, USA; Howard Hughes Medical Institute, Whitehead Institute, Cambridge, MA 02142, USA
- Sidaly Phou
- Whitehead Institute, Cambridge, MA 02142, USA; Howard Hughes Medical Institute, Whitehead Institute, Cambridge, MA 02142, USA
- Ashley Buscetta
- Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892, USA
- Paul Kruszka
- Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892, USA
- Nicole Banks
- Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892, USA; Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892, USA
- Amalia Dutra
- Cytogenetics and Microscopy Core, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892, USA
- Evgenia Pak
- Cytogenetics and Microscopy Core, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892, USA
- Patricia C. Lasutschinkow
- Focus Foundation, Davidsonville, MD 21035, USA
- Colleen Keen
- Focus Foundation, Davidsonville, MD 21035, USA
- Shanlee M. Davis
- Department of Pediatrics, University of Colorado School of Medicine, Aurora, CO 80045, USA
- Nicole R. Tartaglia
- Department of Pediatrics, University of Colorado School of Medicine, Aurora, CO 80045, USA; Developmental Pediatrics, eXtraOrdinarY Kids Program, Children’s Hospital Colorado, Aurora, CO 80011, USA
- Carole Samango-Sprouse
- Focus Foundation, Davidsonville, MD 21035, USA; Department of Pediatrics, George Washington University, Washington, DC 20052, USA; Department of Human and Molecular Genetics, Florida International University, Miami, FL 33199, USA
- Maximilian Muenke
- Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892, USA
- David C. Page
- Whitehead Institute, Cambridge, MA 02142, USA; Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Howard Hughes Medical Institute, Whitehead Institute, Cambridge, MA 02142, USA; Corresponding author
- Journal volume & issue
-
Vol. 3,
no. 2
p. 100259
Abstract
Summary: 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.
