title: Domains of genome-wide gene expression dysregulation in Down's syndrome.
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.
authors.affiliation: 1] Department of Genetic Medicine and Development, University of Geneva Medical School, University Hospitals of Geneva, 1211 Geneva, Switzerland [2].
authors.forename: Audrey
authors.initials: A
authors.lastname: Letourneau
authors.affiliation: 1] Department of Genetic Medicine and Development, University of Geneva Medical School, University Hospitals of Geneva, 1211 Geneva, Switzerland [2].
authors.forename: Federico A
authors.initials: FA
authors.lastname: Santoni
authors.affiliation: Department of Genetic Medicine and Development, University of Geneva Medical School, University Hospitals of Geneva, 1211 Geneva, Switzerland.
authors.forename: Ximena
authors.initials: X
authors.lastname: Bonilla
authors.affiliation: Department of Genetic Medicine and Development, University of Geneva Medical School, University Hospitals of Geneva, 1211 Geneva, Switzerland.
authors.forename: M Reza
authors.initials: MR
authors.lastname: Sailani
authors.affiliation: Center for Genomic Regulation, University Pompeu Fabra, 08003 Barcelona, Spain.
authors.forename: David
authors.initials: D
authors.lastname: Gonzalez
authors.affiliation: Division of Gene Regulation, Netherlands Cancer Institute, 1066 CX Amsterdam, The Netherlands.
authors.forename: Jop
authors.initials: J
authors.lastname: Kind
authors.affiliation: 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.
authors.forename: Claire
authors.initials: C
authors.lastname: Chevalier
authors.affiliation: Department of Genome Sciences, University of Washington, Seattle, Washington 98195, USA.
authors.forename: Robert
authors.initials: R
authors.lastname: Thurman
authors.affiliation: Department of Genome Sciences, University of Washington, Seattle, Washington 98195, USA.
authors.forename: Richard S
authors.initials: RS
authors.lastname: Sandstrom
authors.affiliation: Stem Cell Research Laboratory, Department of Obstetrics and Gynecology, Geneva University Hospitals, 1211 Geneva, Switzerland.
authors.forename: Youssef
authors.initials: Y
authors.lastname: Hibaoui
authors.affiliation: Department of Genetic Medicine and Development, University of Geneva Medical School, University Hospitals of Geneva, 1211 Geneva, Switzerland.
authors.forename: Marco
authors.initials: M
authors.lastname: Garieri
authors.affiliation: Department of Genetic Medicine and Development, University of Geneva Medical School, University Hospitals of Geneva, 1211 Geneva, Switzerland.
authors.forename: Konstantin
authors.initials: K
authors.lastname: Popadin
authors.affiliation: Department of Genetic Medicine and Development, University of Geneva Medical School, University Hospitals of Geneva, 1211 Geneva, Switzerland.
authors.forename: Emilie
authors.initials: E
authors.lastname: Falconnet
authors.affiliation: Department of Genetic Medicine and Development, University of Geneva Medical School, University Hospitals of Geneva, 1211 Geneva, Switzerland.
authors.forename: Maryline
authors.initials: M
authors.lastname: Gagnebin
authors.affiliation: Department of Genetic Medicine and Development, University of Geneva Medical School, University Hospitals of Geneva, 1211 Geneva, Switzerland.
authors.forename: Corinne
authors.initials: C
authors.lastname: Gehrig
authors.affiliation: Department of Genetic Medicine and Development, University of Geneva Medical School, University Hospitals of Geneva, 1211 Geneva, Switzerland.
authors.forename: Anne
authors.initials: A
authors.lastname: Vannier
authors.affiliation: Department of Genetic Medicine and Development, University of Geneva Medical School, University Hospitals of Geneva, 1211 Geneva, Switzerland.
authors.forename: Michel
authors.initials: M
authors.lastname: Guipponi
authors.affiliation: FASTERIS SA, 1228 Plan-les-Ouates, Switzerland.
authors.forename: Laurent
authors.initials: L
authors.lastname: Farinelli
authors.affiliation: Department of Genetic Medicine and Development, University of Geneva Medical School, University Hospitals of Geneva, 1211 Geneva, Switzerland.
authors.forename: Daniel
authors.initials: D
authors.lastname: Robyr
authors.affiliation: 1] Department of Genetic Medicine and Development, University of Geneva Medical School, University Hospitals of Geneva, 1211 Geneva, Switzerland [2] Swiss Institute of Bioinfomatics, 1211 Geneva, Switzerland.
authors.forename: Eugenia
authors.initials: E
authors.lastname: Migliavacca
authors.affiliation: Department of Genetic Medicine and Development, University of Geneva Medical School, University Hospitals of Geneva, 1211 Geneva, Switzerland.
authors.forename: Christelle
authors.initials: C
authors.lastname: Borel
authors.affiliation: DOE Joint Genome Institute, Walnut Creek, California 94598, USA.
authors.forename: Samuel
authors.initials: S
authors.lastname: Deutsch
authors.affiliation: Stem Cell Research Laboratory, Department of Obstetrics and Gynecology, Geneva University Hospitals, 1211 Geneva, Switzerland.
authors.forename: Anis
authors.initials: A
authors.lastname: Feki
authors.affiliation: Department of Genome Sciences, University of Washington, Seattle, Washington 98195, USA.
authors.forename: John A
authors.initials: JA
authors.lastname: Stamatoyannopoulos
authors.affiliation: 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.
authors.forename: Yann
authors.initials: Y
authors.lastname: Herault
authors.affiliation: Division of Gene Regulation, Netherlands Cancer Institute, 1066 CX Amsterdam, The Netherlands.
authors.forename: Bas
authors.initials: B
authors.lastname: van Steensel
authors.affiliation: Center for Genomic Regulation, University Pompeu Fabra, 08003 Barcelona, Spain.
authors.forename: Roderic
authors.initials: R
authors.lastname: Guigo
authors.affiliation: 1] Department of Genetic Medicine and Development, University of Geneva Medical School, University Hospitals of Geneva, 1211 Geneva, Switzerland [2] iGE3 Institute of Genetics and Genomics of Geneva, 1211 Geneva, Switzerland.
authors.forename: Stylianos E
authors.initials: SE
authors.lastname: Antonarakis
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D002843:Chromatin / Q000737:chemistry / Q000378:metabolism; D002891:Chromosomes, Human, Pair 21 / Q000235:genetics; D033481:Chromosomes, Mammalian / Q000235:genetics; D042522:DNA Replication Timing; D004314:Down Syndrome / Q000235:genetics* / Q000473:pathology; D005260:Female; D005333:Fetus / Q000166:cytology; D005347:Fibroblasts; D005786:Gene Expression Regulation / Q000235:genetics*; D016678:Genome / Q000235:genetics*; D006657:Histones / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000378:metabolism; D008239:Lysine / Q000378:metabolism; D008297:Male; D008745:Methylation; D051379:Mice; D059467:Transcriptome / Q000235:genetics*; D014430:Twins, Monozygotic / Q000235:genetics
chemical_list: D002843:Chromatin; D006657:Histones; D008239:Lysine
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