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.

A genetic cause of Alzheimer disease: mechanistic insights from Down syndrome

“…However, not all genes are dosage sensitive, as homeostasis often prevents a gene from being overexpressed and the regulation of expression is often dependent on environmental context 112 . Furthermore, trisomy 21 causes widespread transcriptional dysregulation 112,113 , which may be the result of aneuploidy rather than of triplication of a specific gene. The importance of this in AD-DS remains unclear.…”

“…This suggests that duplication of APP, and possibly of other genes located nearby, could be epileptogenic; however, as late-onset seizures often follow onset of dementia, they may also be related to synaptic deterioration that results in abnormal synchronization of neuronal networks and hyperexcitability 110 . 112,113 , which may be the result of aneuploidy rather than of triplication of a specific gene. The importance of this in AD-DS remains unclear.…”

The Effects of Varying Chromosome Arm Dosage on Maize Plant Morphogenesis

“…The results of a genome-wide transcriptome analysis of trisomic 21 cells differed from normal diploid cells inasmuch as the trisomy condition appears to have a leveling effect such that chromosomal domains normally exhibiting a high transcript level are decreased and those domains normally exhibiting a low level are increased in their transcript level (Letourneau et al 2014). These researchers also found that the chromosomal domains exhibiting dysregulation of transcription are conserved in the Ts65Dn mouse model of Down syndrome.…”

“…Any such model must accommodate the genomewide trans-acting dosage effects resulting from an increase or a decrease in the copy number of one (B-A) or two (B-A-A) chromosome segments; it must explain how dosage-sensitive regulatory effects are tissue-specific; it must explain how different phenotypic effects occur depending on which chromosome segment is varied; and it should provide insight into the different phenotypic effects observed with different B-A-A translocations and with those B-A-A translocations where trait measurements were increased. The genome-wide gene expression regulatory system described by Letourneau et al (2014) provides a model that may be suitable in a modified form to help explain the maize aneuploidy results. However, the modified model would need to allow for the selective modulation of transcription rates, in particular chromosome transcription domains, so as to accommodate tissue specificity as well as the different phenotypic effects resulting from increased and decreased dosage of different chromosome segments.…”

“…A recent report (Letourneau et al 2014) on genome-wide gene expression dysregulation in human cells trisomic for chromosome 21 may be useful for modeling a genome-wide dosage-sensitive regulatory system function in maize. The results of a genome-wide transcriptome analysis of trisomic 21 cells differed from normal diploid cells inasmuch as the trisomy condition appears to have a leveling effect such that chromosomal domains normally exhibiting a high transcript level are decreased and those domains normally exhibiting a low level are increased in their transcript level (Letourneau et al 2014).…”