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

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  • A Corrigendum to this article was published on 02 December 2015
  • A Corrigendum to this article was published on 02 December 2015

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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Figure 1: Gene expression fold change is organized in chromosomal domains.
Figure 2: Weakly and highly expressed genes contribute differently to the domains.
Figure 3: GEDDs are conserved in iPS cells.
Figure 4: GEDDs are conserved in Ts65Dn mouse model for Down’s syndrome.
Figure 5: Correlation with LADs.
Figure 6: Correlation with replication time domains and H3K4me3 mark.

Accession codes

Primary accessions

Gene Expression Omnibus

Data deposits

All sequencing data have been deposited in the Gene Expression Omnibus (GEO) data repository under accession number GSE55426.

Change history

  • 02 December 2015

    Nature 508, 345–350 (2014); doi:10.1038/nature13200 Owing to a labelling error in the input files, one of the two replicate data sets used for Fig. 5d and e and Supplementary Fig. 6d of this Article was incorrect. We have now repeated the analysis with a correct, independent replicate experiment. This confirms our previous conclusion that there are no detectable differences in nuclear lamina interactions between the normal and trisomy 21 twin cells.

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Acknowledgements

We thank the Swiss National Science Foundation (SNF-144082), the European Research Council (ERC-249968), AnEUploidy and BluePrint EU grants, the Lejeune, and ChildCare foundations for supporting the S.E.A. laboratory. The laboratories of R.G. were supported by Spanish MICINN (BIO2011-26205) and ERC-294653, B.v.S. by NWO-ALW-VICI, Y.He. by CNRS, INSERM, University of Strasbourg and ANR-10-INBS-07, J.A.S. by NIH U54HG007010, and A.F. by Genico and Ernest Boninchi foundation. We thank S. Dahoun and J. L. Blouin for the discordant twins sample collection.

Author information

The project was coordinated by S.E.A. A.L. coordinated/undertook the main laboratory work. F.A.S. coordinated/undertook the main bioinformatics/statistical analyses. X.B. performed ChIP-seq experiments. M.R.S. performed DNA methylation, A.L., F.A.S., M.G., R.G. and D.G. processed NGS data. J.K. and B.v.S. performed DamID experiments. C.C. and Y.He. maintained the mouse colony and contributed mouse samples. R.T., R.S.S. and J.A.S. performed DNase experiments; Y.Hi. and A.F. derived the iPS cells; and K.P., D.R. R.G. and E.M. performed additional statistical analyses. E.F., M.G., C.G., A.V., M.G., L.F., C.B. and S.D. assisted with wet lab experiments and contributed to performing NGS experiments. The main findings were interpreted by S.E.A., A.L. and F.A.S., who also wrote the manuscript. All authors made comments on the manuscript.

Correspondence to Stylianos E. Antonarakis.

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The authors declare no competing financial interests.

Supplementary information

Supplementary Figures

This file contains Supplementary Figures 1-12. (PDF 8032 kb)

Supplementary Table 1

Differential expression analysis results as given by EdgeR. For each gene, the table gives gene coordinates, Ensembl gene ID, gene category, gene symbol, log2 gene expression fold change (T1DS/T2N, all replicates), log2 counts-per-million (logCPM), p-value and false discovery rate (FDR). (XLSX 4151 kb)

Supplementary Table 2

List of GEDDs identified in the twins’ fibroblasts (Rep0). Table gives the domain ID, the names and coordinates of the first genes at the left and right borders of each GEDD, the number of genes included in the domain and the median log2 fold change within the domain. GEDDs were obtained with a smoothing bandwidth of 3%. (XLSX 38 kb)

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Letourneau, A., Santoni, F., Bonilla, X. et al. Domains of genome-wide gene expression dysregulation in Down’s syndrome. Nature 508, 345–350 (2014). https://doi.org/10.1038/nature13200

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