Coupling of Nuclear Translocation to Cell Size Promotes Robustness to Fluctuations in YAP/TAZ Concentration

Abstract

Protein concentrations are not constant across cell sizes; many dilute or concentrate in response to growth. Through quantitative analysis of ~400,000 single cells across ten cell breast epithelial cell lines (including tumour and non-tumour cells), we show that the cytoplasmic and total concentrations of YAP/TAZ, decreases as a function of cell size in G1 and G2. Degradation of YAP/TAZ alone could not explain this phenomenon. Near S-Phase, YAP/TAZ was synthesised in a ploidy and size dependent manner. Theoretical modelling of YAP/TAZ concentration distributions demonstrated the rate of dilution with cell size relates to YAP/TAZ heterogeneity across the population. YAP/TAZ dilution in the cytoplasm was largely robust to perturbations in Rho GTPase and LATS1/2 signalling, whereas the YAP/TAZ nuclear cytoplasmic (n/c) ratio, was not. Alterations to the n/c ratio following perturbation were more commonly driven by cytoplasmic dilution rather than nuclear enrichment. Together, this work reveals how size scaling phenomena may influence the subcellular distribution of transcription factors, and more generally, relates protein dilution to the emergence of non-genetic heterogeneity in cell populations.

Data-modeling the interplay between single cell shape, single cell protein expression, and tissue state

“…The downside of cell morphology is that it is more difficult to biologically interpret and thus it is harder to extract specific biologically meaningful insights. Cell shape is widely studied and can be more easily interpreted (e.g., larger p53-positive tumor cells), validated and linked to specific molecular players (e.g., Jones et al, 2023) and thus was at the focus of our study.…”