Accuracy and limitations of extrinsic noise models to describe gene expression in growing cells

We will discuss about “Accuracy and limitations of extrinsic noise models to describe gene expression in growing cells”, Jia, Chen, and Ramon Grima, bioRxiv (2022).

Abstract: The standard model describing the fluctuations of mRNA numbers in single cells is the telegraph model which includes synthesis and degradation of mRNA, and switching of the gene between active and inactive states. While commonly used, this model does not describe how fluctuations are influenced by the cell cycle phase, cellular growth and division, and other crucial aspects of cellular biology. Here we derive the analytical time-dependent solution of a stochastic model that explicitly considers various sources of intrinsic and extrinsic noise: switching between inactive and active states, doubling of gene copy numbers upon DNA replication, dependence of the mRNA synthesis rate on cellular volume, gene dosage compensation, partitioning of molecules during cell division, cell-cycle duration variability, and cell-size control strategies. We show that generally the analytical distribution of transcript numbers in steady-state growth cannot be accurately approximated by the steady-state solution of extrinsic noise models, i.e. a telegraph model with parameters drawn from probability distributions. This is because the mRNA lifetime is often not small enough compared to the cell cycle duration to erase the memory of division and replication. Accurate approximations are possible when this memory is weak, e.g. for genes with bursty expression and for which there is sufficient gene dosage compensation when replication occurs.