Domains of genome-wide gene expression dysregulation in Down syndrome. S. E. Antonarakis1, A. Letourneau1, F. A. Santoni1, X. Bonilla1, M. R. Sailani1, D. Robyr1, D. Gonzalez2, J. Kind3, C. Chevalier4, R. Thurman5, R. S. Sandstrom5, Y. Hibaoui6, M. Garieri1, K. Popadin1, E. Falconnet1, M. Gagnebin1, M. Gehrig1, A. Vannier1, M. Guipponi1, E. Migliavacca1, S. Deutsch1, A. Feki6, J. Stamatoyannopoulos5, Y. Herault4, B. van Steensel3, R. Guigo2, C. Borel1 1) Genetic Medicine, University of Geneva, Geneva, Switzerland; 2) Center for Genomic Regulation, University Pompeu Fabra, Barcelona, Spain; 3) Division of Gene Regulation, Netherlands Cancer Institute, Amsterdam, The Netherlands; 4) Institut de Génétique Biologie Moléculaire et Cellulaire, Translational medicine and Neuroscience program, IGBMC, and Université de Strasbourg, France; 5) Department of Genome Sciences, University of Washington, Seattle, Washington, USA; 6) Stem Cell Research Laboratory, Department of Obstetrics and Gynecology, Geneva University Hospitals, Geneva, Switzerland.
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. We have shown that the differential expression between the twins is organized in domains along all chromosomes that are either upregulated or downregulated (Nature 2014; PMID 24740065). 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 Downs 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 GEDDs may therefore contribute to some trisomy 21 phenotypes. GEDDs could be the result of genes on chromosome 21, or to the extra chromosomal material. To distinguish between the two possibilities, we use i/ a series of mouse models of human trisomy 21 with different partial trisomies and monosomies; ii/ targeted disruption of one allele of candidate genes in a trisomy background; iii/ fibroblasts from mosaic trisomies 13 and 18.
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