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.
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Many genes throughout the genome are altered in DS, confirming and extending previous findings that non-HSA21 genes may contribute significantly to trisomy 21 phenotypes.
“Together, these studies demonstrate that many genes throughout the genome are altered in DS, confirming and extending previous findings that non-HSA21 genes may contribute significantly to trisomy 21 phenotypes (Letourneau et al., 2014; Lockstone et al., 2007).”
From Down Syndrome Developmental Brain Transcriptome Reveals Defective Oligodendrocyte Differentiation and Myelination (2016) · cites this paper as Letourneau et al., 2014
Prior transcriptome studies of DS brains or derived pluripotent stem cells are limited by sparse genome coverage, numbers of samples or developmental time points, and potential variances between in vitro and in vivo gene regulation.
“While several reports have investigated gene expression in postmortem human DS brains or derived pluripotent stem cells (Letourneau et al., 2014; Lockstone et al., 2007; Mao et al., 2003, 2005), these studies are limited by sparse genome coverage, numbers of samples or developmental time points, and potential variances between in vitro and in vivo gene regulation.”
From Down Syndrome Developmental Brain Transcriptome Reveals Defective Oligodendrocyte Differentiation and Myelination (2016) · cites this paper as Letourneau et al., 2014
These GEDDs were not observable when comparing grouped samples due to gene expression differences between individuals.
“These GEDDs were not observable when comparing grouped samples due to gene expression differences between individuals, and this is consistent with our results (Figure S4).”
From Down Syndrome Developmental Brain Transcriptome Reveals Defective Oligodendrocyte Differentiation and Myelination (2016) · cites this paper as Letourneau et al. (2014)
The DS altered gene expression follows a consistent pattern, with increased and decreased gene-expression levels alternating across large chromosomal segments (GEDDs).
“It has been recently shown by Letourneau et al. (2014) in fibroblasts from monozygotic twins discordant for trisomy 21, that the DS altered gene expression follows a consistent pattern, with increased and decreased gene-expression levels alternating across large chromosomal segments, which they named gene expression dysregulation domains (GEDDs).”
From Down Syndrome Developmental Brain Transcriptome Reveals Defective Oligodendrocyte Differentiation and Myelination (2016) · cites this paper as Letourneau et al. (2014)
T21 impacts gene expression across the genome.
“However, unbiased analyses using omics technology have recently revealed that T21 impacts gene expression across the genome39,74,143,156–159.”
From Consequences of trisomy 21 for brain development in Down syndrome (2024) · cites this paper as [156]
Transcript levels for the analyzed acid hydrolases are comparable in 2N and DS fibroblasts.
“our RNA-Seq analyses, combined with previously published RNA-Seq data (Letourneau et al., 2014;Sullivan et al., 2016), showed transcript levels for the analyzed acid hydrolases to be comparable in 2N and DS fibroblasts”
From Lysosomal Dysfunction in Down Syndrome Is APP-Dependent and Mediated by APP-βCTF (C99) (2019) · cites this paper as Letourneau et al., 2014
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References 57 · Cited by 319
- Authors
- Letourneau, A., Santoni, F. A., Bonilla, X., Sailani, M. R., Gonzalez, D., Kind, J., Chevalier, C., Thurman, R., Sandstrom, R. S., Hibaoui, Y., Garieri, M., Popadin, K., Falconnet, E., Gagnebin, M., Gehrig, C., Vannier, A., Guipponi, M., Farinelli, L., Robyr, D., Migliavacca, E., Borel, C., Deutsch, S., Feki, A., Stamatoyannopoulos, J. A., Herault, Y., van Steensel, B., Guigo, R., & Antonarakis, S. E.
- Affiliations
- University of Geneva (CH)
- The Netherlands Cancer Institute (NL)
- Centre National de la Recherche Scientifique (FR)
- University of Washington (US)
- University Hospital of Geneva (CH)
- Empenn (FR)
- Joint Genome Institute (US)
- Corresponding author
- Antonarakis, Stylianos E.
- ORCID
- Venue
- Nature
- Published
- 2014-04-16
- Volume
- 508
- Issue
- 7496
- Pages
- 345-350
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- OpenAlex
- W2077252523
- Cited by
- 319
- References
- 57
- Citations by year
- 2026: 13 · 2025: 28 · 2024: 19 · 2023: 25 · 2022: 29 · 2021: 38 · 2020: 22 · 2019: 28 · 2018: 17 · 2017: 17 · 2016: 36 · 2015: 29 · 2014: 18
- FWCI
- 33.03
- Type
- journal article
- Language
- en
- Update notices
- correction (2015-12-02)
- Open access
- closed
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- Archive ouverte UNIGE (University of Geneva) (publishedVersion)
- HAL (submittedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- IRIS (submittedVersion)
- SERVAL (Université de Lausanne) (submittedVersion)
- Archive ouverte UNIGE (University of Geneva) (submittedVersion)
- Funders
- Agence Nationale de la Recherche (ANR-10-INBS-0007)
- National Human Genome Research Institute (U54HG007010)
- Topics
- Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Down syndrome and intellectual disability research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomic variations and chromosomal abnormalities
- Keywords
- syndromes, Down syndrome, fetal fibroblasts, Ts65Dn mouse model, lamina-associated domains, replication domains, H3K4me3, chromatin environment, transcriptome, induced pluripotent stem cells, cognitive impairment, chromosome 21
- MeSH terms
- Animals, Cells, Cultured, Chromatin, Chromosomes, Human, Pair 21, Down Syndrome, Female, Fetus, Fibroblasts, Gene Expression Regulation, Histones, Humans, Lysine, Male, Methylation, Twins, Monozygotic, Genome, Chromosomes, Mammalian, DNA Replication Timing, Mice, Induced Pluripotent Stem Cells, Transcriptome
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