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Down's extra chromosome disrupts genome balance
About one per eight hundred births is a Down syndrome - trisomy 21 - child. It is the most frequent genetic cause of intellectual disability and results from a third copy of chromosome 21 (1% of the human genome).
A study conducted by Stylianos Antonarakis and his team in the Department of Genetic Medicine and Development at the University of Geneva (UNIGE) Faculty of Medicine, and published in Nature, shed light on how the extra chromosome 21 upsets the equilibrium of the entire genome, causing a wide variety of pathologies.
Despite much research, the exact mechanisms causing various symptoms associated with Down syndrome remain a mystery.
According to a hypothesis called gene dosage disequilibrium, the presence of a third chromosome 21 could influence the expression of all the other genes in the genome.
This extra genetic material could disrupt the process through which information carried in the genes is decoded, therefore modifying the cellular function.
Based on this hypothesis, several research groups have tried to identify changes in gene expression within trisomic cells and link them with symptoms seen in patients. However, as the level of most gene expression varies from one person to another, it is extremely difficult to discriminate between changes exclusively linked to trisomy 21 and those due to natural variation between individuals.
Comparing Identical Twins
At UNIGE, Stylianos Antonarakis's team has examined the genomes of two identical twins both having the exact same genetic makeup, except for the extra chromosome 21 present in one. Indeed, the chromosome 21 distribution error can take place during an early cell division, after the original fertilized egg splits into twins.
To compare gene expression levels between the twins, UNIGE researchers used recent, high-throughput sequencing and biotechnological tools developed within the Department of Genetic Medicine and Development. Working in collaboration with scientists in Strasbourg, Barcelona, Amsterdam, and Seattle, they were able to eliminate individual variations between the twins and identify only changes in gene expression exclusively due to trisomy 21.
Small chromosome, big consequences
They noticed that the expression of genes located on all chromosomes, other than chromosome 21, were disturbed in the trisomic twin's cells. "We were very surprised by this result," explains Audrey Letourneau, who co-authored this study. "It does seem that this extra little chromosome has a huge influence on the entire genome."
Typically, chromosomes are divided into domains that contain genes with similar levels of RNA production. RNA is the molecule which transcribes the information contained in DNA into mRNA, before translating mRNA into proteins with precise functions. In the twin with Down syndrome, chromosome domains can be over-expressed and under-expressed when compared to those of the healthy twin.
Comparing their results with data previously published by other research groups, UNIGE researchers noticed that this specific chromosomes organization correlates with DNA position in the cell nucleus. Therefore, domains over-expressed in the twin with Down syndrome correspond to portions of DNA known to primarily interact with the nucleus periphery.
This study therefore shows for the first time that the DNA position in the nucleus or the biochemical characteristics of DNA-proteins interactions in the trisomic cells is modified, leading to changes in the gene expression profile.
"These changes do not only affect chromosome 21, but the entire genome. The presence of about 1% of extra genetic material in the trisomic cells hence modifies the function of the whole genome, and disrupts the general equilibrium of gene expression. We could make an analogy with climate change», adds Professor Antonarakis. «Even if the temperature rises by only one or two degrees, it will rain a lot less in the tropics, and a lot more in temperate zones. Global climate equilibrium can thus be disrupted by a tiny element."
Federico Santoni, study co-author, Department of Genetic Medicine and Development, University of Geneva Medical School
This study presents a new understanding of the molecular mechanisms that explain the symptoms of Down syndrome. The UNIGE team will now continue its research to understand molecular mechanisms at stake, and link this disrupted gene expression with the phenotypes associated with Down syndrome. The end goal of this research is to find ways to revert the dysregulation of cellular gene expression back to normal, with the objective to correct the cellular abnormalities in this disease. Progress in this field could also be applied to other diseases with genome imbalance.
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.
This study, which lasted several years, received financial support from the Swiss National Science Foundation (FNS) and the European Research Council (ERC).
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