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

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, Konstantin Popadin, Emilie Falconnet, Maryline Gagnebin, Corinne Gehrig, Anne Vannier, Michel Guipponi, Laurent Farinelli, Daniel Robyr, Eugenia Migliavacca, Christelle Borel, Samuel Deutsch, Anis Feki, John A. Stamatoyannopoulos, Yann Herault, Bas van Steensel, Roderic Guigo and Stylianos E. Antonarakis ()
Additional contact information
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
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

Nature, 2014, vol. 508, issue 7496, 345-350

Abstract: 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.

Date: 2014
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DOI: 10.1038/nature13200

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