Abstract
BackgroundAneuploidy, or abnormal chromosome numbers, severely alters cell physiology and is widespread in cancers and other pathologies. Using model cell lines engineered to carry one or more extra chromosomes, it has been demonstrated that aneuploidy per se impairs proliferation, leads to proteotoxic as well as replication stress and triggers conserved transcriptome and proteome changes.ResultsIn this study, we analysed for the first time miRNAs and demonstrate that their expression is altered in response to chromosome gain. The miRNA deregulation is independent of the identity of the extra chromosome and specific to individual cell lines. By cross-omics analysis we demonstrate that although the deregulated miRNAs differ among individual aneuploid cell lines, their known targets are predominantly associated with cell development, growth and proliferation, pathways known to be inhibited in response to chromosome gain. Indeed, we show that up to 72% of these targets are downregulated and the associated miRNAs are overexpressed in aneuploid cells, suggesting that the miRNA changes contribute to the global transcription changes triggered by aneuploidy. We identified hsa-miR-10a-5p to be overexpressed in majority of aneuploid cells. Hsa-miR-10a-5p enhances translation of a subset of mRNAs that contain so called 5’TOP motif and we show that its upregulation in aneuploids provides resistance to starvation-induced shut down of ribosomal protein translation.ConclusionsOur work suggests that the changes of the microRNAome contribute on one hand to the adverse effects of aneuploidy on cell physiology, and on the other hand to the adaptation to aneuploidy by supporting translation under adverse conditions.
Highlights
Aneuploidy, or abnormal chromosome numbers, severely alters cell physiology and is widespread in cancers and other pathologies
Deregulation of miRNAome in human aneuploid model cell lines To determine the effects of chromosome gain on miRNA expression in human cells, we used a series of cells derived from HCT116 and RPE1 cell lines that contain one or more extra copies of different chromosomes ([5, 9, 12], Fig. 1a, see Methods for more details)
We identified from 23 to 74 significantly deregulated miRNAs (Table 2)
Summary
Aneuploidy, or abnormal chromosome numbers, severely alters cell physiology and is widespread in cancers and other pathologies. Using model cell lines engineered to carry one or more extra chromosomes, it has been demonstrated that aneuploidy per se impairs proliferation, leads to proteotoxic as well as replication stress and triggers conserved transcriptome and proteome changes. A balanced karyotype is essential for cell viability and aneuploidy, characterized by unbalanced changes in chromosome numbers and sub-chromosomal structural variations, has often profound detrimental consequences for cell physiology. Aneuploidy in somatic cells is frequently associated with cancer, as 70% of haematopoietic and 90% of solid cancers show an abnormal karyotype [2, 3]. Given that the triggers of the transcriptional deregulations remain unclear, we asked whether microRNA (miRNA) regulation is involved in the response to aneuploidy.
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