Noise in eukaryotic gene expression

Abstract

Transcription in eukaryotic cells has been described as quantal, with pulses of messenger RNA produced in a probabilistic manner. This description reflects the inherently stochastic nature of gene expression, known to be a major factor in the heterogeneous response of individual cells within a clonal population to an inducing stimulus. Here we show in Saccharomyces cerevisiae that stochasticity (noise) arising from transcription contributes significantly to the level of heterogeneity within a eukaryotic clonal population, in contrast to observations in prokaryotes, and that such noise can be modulated at the translational level. We use a stochastic model of transcription initiation specific to eukaryotes to show that pulsatile mRNA production, through reinitiation, is crucial for the dependence of noise on transcriptional efficiency, highlighting a key difference between eukaryotic and prokaryotic sources of noise. Furthermore, we explore the propagation of noise in a gene cascade network and demonstrate experimentally that increased noise in the transcription of a regulatory protein leads to increased cell-cell variability in the target gene output, resulting in prolonged bistable expression states. This result has implications for the role of noise in phenotypic variation and cellular differentiation.

Genotype networks shed light on evolutionary constraints

“…Such short sequences can evolve rapidly and might endow regulatory circuits with flexible, almost unconstrained phenotypes. On the other hand, factors such as ubiquitous molecular noise inside a cell might constrain attainable patterns of gene expression and molecular activities [67][68][69].…”

“…Canalizing selection disfavors phenotypes that deviate from a given, optimal phenotype, whether they arise through rare genetic perturbations or through more frequent non-genetic perturbations, such as gene expression noise [68,69,78,79]. Sustained canalizing selection can increase the robustness of an evolving population to genetic and non-genetic perturbations [80,81].…”

“…Such short sequences can evolve rapidly and might endow regulatory circuits with flexible, almost unconstrained phenotypes. On the other hand, factors such as ubiquitous molecular noise inside a cell might constrain attainable patterns of gene expression and molecular activities [67][68][69].The processes that create phenotypes from genotypes for the systems I examine here are protein folding, the dynamically changing regulatory interactions within regulatory circuits and the chemical synthesis of biomass molecules. These processes are the analog of 'development' for these systems.…”

Distinct noise-controlling roles of multiple negative feedback mechanisms in a prokaryotic operon system

“…fluorescent reporters and single-cell imaging techniques) in recently years have allowed stochastic gene expression to be quantified in vivo [1,[5][6][7]. These elegant experiments, along with theoretical studies [8],…”

“…Intrinsic noise originates from the randomness in the biochemical processes that take place in gene expression whereas extrinsic noise comes from fluctuations in other factors that influence gene expression. Effort has since been carried out by different groups aiming to separate one type of noise from another experimentally [5,6] and theoretically [8,9].…”