The deregulated microRNAome contributes to the cellular response to aneuploidy

Abstract

Background: 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. Results: In 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.

Dynamic chromosomal interactions and control of heterochromatin positioning by Ki‐67

“…Similar plot as (Fig 4C ), but instead highlighting for every gene the expression level (in log 10 FPKM). Expression data are used from (Encode Project Consortium, 2012 ; Slaats et al , 2015 ; Harenza et al , 2017 ; Kelso et al , 2017 ; Sun et al , 2017 ; Dai et al , 2018 ; Durrbaum et al , 2018 ; see Materials and Methods ).…”

Dynamic chromosomal interactions and control of heterochromatin positioning by Ki-67

“… (F) Similar plot as ( Fig 4C ), but instead highlighting for every gene the expression level (in log 10 FPKM). Expression data are used from (Consortium, 2012; Dai et al , 2018; Durrbaum et al , 2018; Harenza et al , 2017; Kelso et al , 2017; Slaats et al , 2015; Sun et al , 2017) (see Methods).…”

Tolerance of Chromosomal Instability in Cancer: Mechanisms and Therapeutic Opportunities

“…2). Similarly, recent analysis of aneuploid cancer cells has shown that these cells modulate their phospho-proteome and the microRNAome to adapt their physiology to the adverse effects of aneuploidy (65,66). Although evidence of proteome homeostasis as an aneuploidy maintenance mechanism has been gained from in vitro systems, studies in breast cancer supports the notion that attenuation of the effect of chromosome imbalances on protein levels also occurs in human tumors (67).…”