Unique features of the transcriptional response to model aneuploidy in human cells

Abstract

BackgroundAneuploidy, a karyotype deviating from multiples of a haploid chromosome set, affects the physiology of eukaryotes. In humans, aneuploidy is linked to pathological defects such as developmental abnormalities, mental retardation or cancer, but the underlying mechanisms remain elusive. There are many different types and origins of aneuploidy, but whether there is a uniform cellular response to aneuploidy in human cells has not been addressed so far.ResultsHere we evaluate the transcription profiles of eleven trisomic and tetrasomic cell lines and two cell lines with complex aneuploid karyotypes. We identify a characteristic aneuploidy response pattern defined by upregulation of genes linked to endoplasmic reticulum, Golgi apparatus and lysosomes, and downregulation of DNA replication, transcription as well as ribosomes. Strikingly, complex aneuploidy elicits the same transcriptional changes as trisomy. To uncover the triggers of the response, we compared the profiles with transcription changes in human cells subjected to stress conditions. Interestingly, we found an overlap only with the response to treatment with the autophagy inhibitor bafilomycin A1. Finally, we identified 23 genes whose expression is significantly altered in all aneuploids and which may thus serve as aneuploidy markers.ConclusionsOur analysis shows that despite the variability in chromosome content, aneuploidy triggers uniform transcriptional response in human cells. A common response independent of the type of aneuploidy might be exploited as a novel target for cancer therapy. Moreover, the potential aneuploidy markers identified in our analysis might represent novel biomarkers to assess the malignant potential of a tumor.

Reproductive isolation in a nascent species pair is associated with aneuploidy in hybrid offspring

“…A recent study also found a consistent transcriptional profile within species that was independent of the specific chromosome aberration investigated [53]. In general, many organisms for which the aneuploidy effect has been studied were found to display developmental abnormalities, in addition to a transcriptional signature involving protein synthesis, inflammatory and stress responses [34,54]. Not surprisingly, this signature was also found in lake whitefish malformed backcrosses [28], in addition to a downregulation of essential developmental genes [26].…”

Chromosomal Instability as a Driver of Tumor Heterogeneity and Evolution

“…Work in yeast and human cells shows that aneuploidy induces metabolic and proteotoxic stress, which translate into lower proliferation rates (Torres et al 2007(Torres et al , 2010Williams et al 2008;Oromendia et al 2012;Sheltzer et al 2012;Sheltzer 2013;Dürrbaum et al 2014). Given the increased metabolic demand and oxidative stress imparted by aneuploidy, this has led some to postulate that aneuploidy may serve as one of the triggers for the Warburg effect often seen in cancer, whereby cells shift away from oxidative phosphorylation toward aerobic glycolysis (Vander Heiden et al 2009;Siegel and Amon 2012).…”

The deregulated microRNAome contributes to the cellular response to aneuploidy

“…The physiological changes in response to an unbalanced karyotype are multifold, including impaired proliferation, replication stress and proteotoxic stress that is characterized by changes in protein stoichiometry, reduced protein folding capacity and by activation of autophagy [4][5][6][7][8][9][10][11][12][13]. The physiological response to aneuploidy goes hand in hand with a transcriptional response that is manifested in a conserved pathway deregulation [14,15]. What triggers these changes in gene expression and how exactly this specific response is modulated has not been clarified so far.…”