Scaling of cellular proteome with ploidy

Abstract

Ploidy changes are frequent in nature and contribute to evolution, functional specialization and tumorigenesis (1,2). Analysis of model organisms of different ploidies revealed that increased ploidy leads to an increase in cell and nuclear volume, reduced proliferation (2-4), metabolic changes (5), lower fitness (6,7), and increased genomic instability (8,9), but the underlying mechanisms remain poorly understood. To investigate how the gene expression changes with cellular ploidy, we analyzed isogenic series of budding yeasts from 1N to 4N. We show that mRNA and protein abundance scales allometrically with ploidy, with tetraploid cells showing only threefold increase in proteins compared to haploids. This ploidy-specific scaling occurs via decreased rRNA and ribosomal protein abundance and reduced translation. We demonstrate that the Tor1 activity is reduced with increasing ploidy, which leads to rRNA gene repression via a novel Tor1-Sch9-Tup1 signaling pathway. mTORC1 and S6K activity are also reduced in human tetraploid cells and the concomitant increase of the Tup1 homolog Tle1 downregulates the rDNA transcription. Our results revealed a novel conserved mTORC1-S6K-Tup1/Tle1 pathway that ensures proteome remodeling in response to increased ploidy.

Characterization of proteome-size scaling by integrative omics reveals mechanisms of proliferation control in cancer

“…Expression and phosphorylation of G2/M, DNA-associated and biosynthetic peptides exhibited a clear sub-scaling relationship with cell size across two independent panels of melanoma cell lines, whilst expression of lipid metabolic genes and phosphorylation of cytoskeletal regulators showed the reverse. This is in strong agreement with numerous recent studies investigating the relationships between cell size and gene/peptide expression; identifying histones as sub-scaling components (Amodeo et al, 2015), observing an upregulation of lipid metabolism in larger cell lines (Neurohr et al, 2019), noting a decreased abundance of translational components and translation rate in large polyploid cells (Yahya et al, 2021) and a full proteome survey of scaling components in human lung fibroblasts (Lanz et al, 2021).…”

“…Many proteins have been shown to ‘super’ or ‘sub’ scale (mass fraction increases/decreases) with cell size (Amodeo et al, 2015; Lanz et al, 2021) beyond a small set of proliferative regulators. Indeed, recent studies point to histones (Amodeo et al, 2015; Swaffer et al, 2021), translational components (Yahya et al, 2021) and several metabolic elements (Lanz et al, 2021; Neurohr et al, 2019) sub/super scaling with cell size. Not all these proteins will act as size ‘rulers’, and may instead influence their activity.…”

Organellar transcripts dominate the cellular mRNA pool across plants of varying ploidy levels

“…Standard RNA-seq only measures relative gene expression, but it is possible to use RNA-seq to estimate changes in absolute expression levels per cell by quantifying the number of cells used in RNA extractions and applying spike-in controls during the sequencing process (63, 64). Given the increased cell size in polyploids, total transcriptome and proteome sizes are expected to scale allometrically with ploidy (65, 66), but how these scaling relationships affect many key features of cytonuclear interactions have yet to be explored in polyploid plants.…”

Diacylglycerol at the inner nuclear membrane fuels nuclear envelope expansion in closed mitosis

“…The increase in the relative proportion of diploids in dgk1 Δ cultures over time suggested an intriguing possibility that S. pombe diploids are less sensitive to the loss of Dgk1 activity than haploids. Such scaling relationships resulting in metabolic and phenotypic differences between cells of different ploidy do exist (Yahya et al, 2021), e.g., S. pombe cells exhibit a more coherent cellular geometry scaling when diploidized (Gu and Oliferenko, 2019).…”

“…Although cell size control and homeostasis in haploid S. pombe have been extensively studied, the impact of diploidization on S. pombe physiology and metabolism is less understood. Cell size and ploidy have previously been shown to influence cellular fitness via the cumulative reorganization of the proteome and organelle content (Gu and Oliferenko, 2019; Cheng et al, 2021; Gu and Oliferenko, 2021; Yahya et al, 2021). Changes in metabolism and/or the transmembrane transport efficiency (e.g., due to the decreased surface area-to-volume ratio of diploids), may contribute to different metabolic requirements in diploids.…”