Consequences of aneuploidy in human fibroblasts with trisomy 21

Abstract

An extra copy of chromosome 21 causes Down syndrome, the most common genetic disease in humans. The mechanisms contributing to aneuploidy-related pathologies in this syndrome, independent of the identity of the triplicated genes, are not well defined. To characterize aneuploidy-driven phenotypes in trisomy 21 cells, we performed global transcriptome, proteome, and phenotypic analyses of primary human fibroblasts from individuals with Patau (trisomy 13), Edwards (trisomy 18), or Down syndromes. On average, mRNA and protein levels were increased by 1.5-fold in all trisomies, with a subset of proteins enriched for subunits of macromolecular complexes showing signs of posttranscriptional regulation. These results support the lack of evidence for widespread dosage compensation or dysregulation of chromosomal domains in human autosomes. Furthermore, we show that several aneuploidy-associated phenotypes are present in trisomy 21 cells, including lower viability and increased dependency on serine-driven lipid synthesis. Our studies establish a critical role of aneuploidy, independent of triplicated gene identity, in driving cellular defects associated with trisomy 21.

Modulation of Global Gene Expression by Aneuploidy and CNV of Dosage Sensitive Regulatory Genes

“…We also found that aneuploidy states affect cell fate commitment and determination, and influence the development of multiple organs and systems (Figures 2D and 3), which is consistent with the fact that aneuploidy variation usually severely affects the growth and development of organisms [37,38]. Protein stability in aneuploidy cells is also affected, possibly because aneuploidy interferes with protein synthesis and alters sensitivity to protein folding, leading to protein degradation [57,69]. We found that aberrantly expressed genes in Drosophila aneuploidy enriched the function of protein ubiquitination (Figures 2D and 3), revealing that aneuploidy may affect protein degradation by regulating the ubiquitination process.…”

“…In various studies, common characteristics of aneuploidy driven by genomic imbalance have been identified, such as altered metabolism, lower viability, genomic instability, and altered proteostasis [57,69,70]. In this study, we found that a number of metabolic processes in Drosophila are affected by aneuploidy states, such as organic acid and carbohydrate metabolic process.…”

Establishment and Characterization of a Novel Fibroblastic Cell Line (SCI13D) Derived from the Broncho-Alveolar Lavage of a Patient with Fibrotic Hypersensitivity Pneumonitis

“…Given that chromosome 10 harbors the FGF2R gene, presumably higher levels of this receptor, due to the presence of an extra chromosome 10, may lead to overgrowth of a proliferative clone. Although it is still unclear how aneuploidies may control the expression and transcriptional activities of the genes encompassed within the extra chromosome, Sunyoung Hwang and coworkers recently demonstrated that their mRNA levels increase proportionally with gene copy numbers and that mechanisms required to compensate for the gene expression of an extra copy of a human autosome do not seem to be engaged [30]. SCI13D expressed higher mRNA levels of FGFR2 than the MRC5 lung control cell line; however, further investigations would be of help to better establish a potential link between the presence of an extra chromosome 10 and its putative selective advantage for cell expansion.…”

Four layer multi-omics reveals molecular responses to aneuploidy in Leishmania

“…However, through perturbation of regulatory networks, these changes might also affect transcripts and proteins encoded by genomic regions unaffected by aneuploidy. These were previously defined as 'trans-effects' and have been observed on the transcriptional level in diverse species, including humans, yeast, maize, and Arabidopsis [47][48][49][50] . Here we investigated the extend of trans-effects in Leishmania by comparing and characterizing the fractions of differential transcripts and proteins coming from aneuploid chromosomes, i.e.…”