GSE107997
Membrane stress and perturbed nutrient homeostasis as common attributes of heterogeneous aneuploidy
Aneuploidy, the state of having unbalanced chromosome copy numbers, represents a large repertoire of genome alteration that leads to phenotype variation and enables eukaryotic microbes and cancer cells to adapt to stress or acquire drug resistance. Distinct pattern of gene expression and phenotypes associated with individual karyotype have prevented easy identification of common properties caused by aneuploidy. In this study, we conducted a unique transcriptomic analysis aimed to eliminate the direct DNA dosage effect on gene expression across heterogeneous aneuploid populations. This analysis uncovered a gene expression signature associated with heterogeneous aneuploidy that strongly resembles those previously identified for cell populations under hypo-osmotic stress. Cell biological and biophysical measurements confirmed the presence of plasma membrane stress in heterogeneous aneuploid cell populations, which impairs endocytosis. Through a genome-wide screen for gene deletions that alter the growth of heterogeneous aneuploid populations, we identified a genetic dependency of aneuploid growth on members of the arrestin family that promote endocytic recycling of nutrient transporters in the plasma membrane. Experimental measurements and mathematical modeling demonstrated a dysregulation of nutrient homeostasis as a common defect that results from the biophysical ailment of aneuploid cells. Overall design: Used RNA-Seq to identify an aneuploidy-associated gene expression signature by comparing the transcriptomes of karyotypically heterogeneous aneuploid populations to euploid control populations.