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Domains of genome-wide gene expression dysregulation in Down’s syndrome

Author

Listed:
  • Audrey Letourneau

    (University of Geneva Medical School, University Hospitals of Geneva, 1211 Geneva, Switzerland)

  • Federico A. Santoni

    (University of Geneva Medical School, University Hospitals of Geneva, 1211 Geneva, Switzerland)

  • Ximena Bonilla

    (University of Geneva Medical School, University Hospitals of Geneva, 1211 Geneva, Switzerland)

  • M. Reza Sailani

    (University of Geneva Medical School, University Hospitals of Geneva, 1211 Geneva, Switzerland)

  • David Gonzalez

    (Center for Genomic Regulation, University Pompeu Fabra, 08003 Barcelona, Spain)

  • Jop Kind

    (Netherlands Cancer Institute, 1066 CX Amsterdam, The Netherlands)

  • Claire Chevalier

    (AneuPath 21, Institut de Génétique Biologie Moléculaire et Cellulaire, Translational medicine and Neuroscience program, IGBMC, ICS, PHENOMIN, CNRS, INSERM, Université de Strasbourg, UMR7104, UMR964, 1 rue Laurent Fries, 67404 Illkirch, France)

  • Robert Thurman

    (University of Washington)

  • Richard S. Sandstrom

    (University of Washington)

  • Youssef Hibaoui

    (Stem Cell Research Laboratory, Geneva University Hospitals, 1211 Geneva, Switzerland)

  • Marco Garieri

    (University of Geneva Medical School, University Hospitals of Geneva, 1211 Geneva, Switzerland)

  • Konstantin Popadin

    (University of Geneva Medical School, University Hospitals of Geneva, 1211 Geneva, Switzerland)

  • Emilie Falconnet

    (University of Geneva Medical School, University Hospitals of Geneva, 1211 Geneva, Switzerland)

  • Maryline Gagnebin

    (University of Geneva Medical School, University Hospitals of Geneva, 1211 Geneva, Switzerland)

  • Corinne Gehrig

    (University of Geneva Medical School, University Hospitals of Geneva, 1211 Geneva, Switzerland)

  • Anne Vannier

    (University of Geneva Medical School, University Hospitals of Geneva, 1211 Geneva, Switzerland)

  • Michel Guipponi

    (University of Geneva Medical School, University Hospitals of Geneva, 1211 Geneva, Switzerland)

  • Laurent Farinelli

    (FASTERIS SA, 1228 Plan-les-Ouates, Switzerland)

  • Daniel Robyr

    (University of Geneva Medical School, University Hospitals of Geneva, 1211 Geneva, Switzerland)

  • Eugenia Migliavacca

    (University of Geneva Medical School, University Hospitals of Geneva, 1211 Geneva, Switzerland
    Swiss Institute of Bioinfomatics, 1211 Geneva, Switzerland)

  • Christelle Borel

    (University of Geneva Medical School, University Hospitals of Geneva, 1211 Geneva, Switzerland)

  • Samuel Deutsch

    (DOE Joint Genome Institute)

  • Anis Feki

    (Stem Cell Research Laboratory, Geneva University Hospitals, 1211 Geneva, Switzerland)

  • John A. Stamatoyannopoulos

    (University of Washington)

  • Yann Herault

    (AneuPath 21, Institut de Génétique Biologie Moléculaire et Cellulaire, Translational medicine and Neuroscience program, IGBMC, ICS, PHENOMIN, CNRS, INSERM, Université de Strasbourg, UMR7104, UMR964, 1 rue Laurent Fries, 67404 Illkirch, France)

  • Bas van Steensel

    (Netherlands Cancer Institute, 1066 CX Amsterdam, The Netherlands)

  • Roderic Guigo

    (Center for Genomic Regulation, University Pompeu Fabra, 08003 Barcelona, Spain)

  • Stylianos E. Antonarakis

    (University of Geneva Medical School, University Hospitals of Geneva, 1211 Geneva, Switzerland
    iGE3 Institute of Genetics and Genomics of Geneva, 1211 Geneva, Switzerland)

Abstract

Trisomy 21 is the most frequent genetic cause of cognitive impairment. To assess the perturbations of gene expression in trisomy 21, and to eliminate the noise of genomic variability, we studied the transcriptome of fetal fibroblasts from a pair of monozygotic twins discordant for trisomy 21. Here we show that the differential expression between the twins is organized in domains along all chromosomes that are either upregulated or downregulated. These gene expression dysregulation domains (GEDDs) can be defined by the expression level of their gene content, and are well conserved in induced pluripotent stem cells derived from the twins’ fibroblasts. Comparison of the transcriptome of the Ts65Dn mouse model of Down’s syndrome and normal littermate mouse fibroblasts also showed GEDDs along the mouse chromosomes that were syntenic in human. The GEDDs correlate with the lamina-associated (LADs) and replication domains of mammalian cells. The overall position of LADs was not altered in trisomic cells; however, the H3K4me3 profile of the trisomic fibroblasts was modified and accurately followed the GEDD pattern. These results indicate that the nuclear compartments of trisomic cells undergo modifications of the chromatin environment influencing the overall transcriptome, and that GEDDs may therefore contribute to some trisomy 21 phenotypes.

Suggested Citation

  • Audrey Letourneau & Federico A. Santoni & Ximena Bonilla & M. Reza Sailani & David Gonzalez & Jop Kind & Claire Chevalier & Robert Thurman & Richard S. Sandstrom & Youssef Hibaoui & Marco Garieri & Ko, 2014. "Domains of genome-wide gene expression dysregulation in Down’s syndrome," Nature, Nature, vol. 508(7496), pages 345-350, April.
    • Handle: RePEc:nat:nature:v:508:y:2014:i:7496:d:10.1038_nature13200
    DOI: 10.1038/nature13200
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    Cited by:

    1. Sasha L. Fulton & Wendy Wenderski & Ashley E. Lepack & Andrew L. Eagle & Tomas Fanutza & Ryan M. Bastle & Aarthi Ramakrishnan & Emma C. Hays & Arianna Neal & Jaroslav Bendl & Lorna A. Farrelly & Amni , 2022. "Rescue of deficits by Brwd1 copy number restoration in the Ts65Dn mouse model of Down syndrome," Nature Communications, Nature, vol. 13(1), pages 1-17, December.

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