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Scientific article
English

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

Contributors

Letourneau, Audrey; Santoni, Federico; Bonilla Bustillo, Ximena; Sailani, Mohammad Reza; Gonzalez, David; Kind, Jop; Chevalier, Claire; Thurman, Robert; Sandstrom, Richard S; Hibaoui, Youssef; Garieri, Marco; Popadin, Konstantin; Falconnet, Emilie; Gagnebin, Maryline; Gehrig, Corinne; Vannier, Anne; Guipponi, Michel; Farinelli, Laurent; Robyr, Daniel; Migliavacca Voeffray, Eugenia Linda; Borel, Christelle; Deutsch Escalante, Samuel; Feki, Anis; Stamatoyannopoulos, John A; Herault, Yann; van Steensel, Bas; Guigo, Roderic; Antonarakis, Stylianos

Published in

Nature, vol. 508, no. 7496, p. 345-350

Publication date

2014

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.

Keywords

  • Animals
  • Cells, Cultured
  • Chromatin/chemistry/metabolism
  • Chromosomes, Human, Pair 21/genetics
  • Chromosomes, Mammalian/genetics
  • DNA Replication Timing
  • Down Syndrome/genetics/pathology
  • Female
  • Fetus/cytology
  • Fibroblasts
  • Gene Expression Regulation/genetics
  • Genome/genetics
  • Histones/chemistry/metabolism
  • Humans
  • Induced Pluripotent Stem Cells/metabolism
  • Lysine/metabolism
  • Male
  • Methylation
  • Mice
  • Transcriptome/genetics
  • Twins, Monozygotic/genetics

UNIGE affiliation entities

UNIGE research groups

Citation (ISO format)

LETOURNEAU, Audrey et al. Domains of genome-wide gene expression dysregulation in Down’s syndrome. In: Nature, 2014, vol. 508, n° 7496, p. 345–350. doi: 10.1038/nature13200

Main files (1)

Article (Published version)

Identifiers

Journal ISSN

0028-0836
720views
2downloads

Technical informations

Creation

26/11/2014 16:07:00

First validation

26/11/2014 16:07:00

Update

14/03/2023 22:18:37

Status update

14/03/2023 22:18:36

Last indexation

30/10/2024 20:56:33
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