A systems biology perspective on the consequences of aneuploidy in human cells

Background: Aneuploidy, 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. Results: Here 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. Conclusions: Our 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. Background Aneuploidy, or a change in cellular chromosome numbers, has profound effects on the physiology of all eukaryotic cells analyzed to date [1]. Aneuploid yeasts are characterized by slow growth, altered sensitivity to various stresses and increased genomic instability [2-4]. At the same time, aneuploidy drives genetic variability and cellular adaptation capacity in yeast [5,6]. Plants are in general more tolerant to gene dosage changes, yet aneuploidy often impairs their vigour and alters their phenotype [7]. Aneuploid mammals are rarely viable and the sporadic survivors are affected on multiple levels. In humans, aneuploidy is responsible for a substantial proportion of spontaneous abortions and the rare survivors with trisomy of chromosome 13, 18 and 21 (Patau, Edward and Down syndrome, respectively) are severely handicapped; only trisomy 21 is compatible with survival until adulthood [8]. Aneuploidy is also linked to cancer, as nearly 90% of solid tumors and 75% of hematopoietic cancers show abnormal chromosome dosage [9]. Recently it has been shown that the occurrence of aneuploid cells increases with aging [10] and an increased incidence of aneuploidy in the brain has been linked to neurodegenerative diseases [11]. The exact mechanisms underlying the detrimental effects of aneuploidy remain unclear, but it has been convincingly shown that they are caused by the expression of the extra genes on the supernumerary chromosome [3]. In most aneuploid cells the chromosome dosage changes lead to correlating changes in mRNA (e.g. [3,12-15]) as well as on protein levels [6,15,16]. These analyses further * Correspondence: storchov@biochem.mpg. de Group Maintenance of Genome Stability, Max Planck Institute of Biochemistry, Am Klopferspitz 18, Martinsried 82152, Germany Center for Integrated Protein Science Munich, Ludwig-Maximilian-University Munich, Munich 80336, Germany Full list of author information is available at the end of the article © 2014 Dürrbaum et al.; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Dürrbaum et al. BMC Genomics 2014, 15:139 http://www.biomedcentral. com/1471-2164/15/139