Principles of cellular resource allocation revealed by condition-dependent proteome profiling

Metzl-Raz, Eyal; Kafri, Moshe; Yaakov, Gilad; Soifer, Ilya; Gurvich, Yonat; Barkai, Naama

doi:10.1101/124370

Cited by 27 publications

(64 citation statements)

References 61 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Our macroscopic ribosome dynamics model highlights how cells can tune total ribosome number, the fraction of working ribosomes and the rate of translational elongation to achieve the same total protein production rate while balancing other constraints such as reduced amino acid availability or the need to rapidly accelerate growth. This strategy could help explain recent reports of the suboptimality of protein allocation for E. coli in the presence of poor carbon sources 43–46 , the suboptimal expression levels of essential genes in Bacillus subtilis 47 and excess ribosome production in S. cerevisiae 48,49 . Future studies will address the consequences of adaptation strategies in dynamic conditions, for example the generality of optimizing growth rate transitions at the expense of steady-state growth.…”

Section: Discussionmentioning

confidence: 92%

Escherichia coli translation strategies differ across carbon, nitrogen and phosphorus limitation conditions

et al. 2018

View full text Add to dashboard Cite

For cells to grow faster they must increase their protein production rate. Microorganisms have traditionally been thought to accomplish this increase by producing more ribosomes to enhance protein synthesis capacity, leading to the linear relationship between ribosome level and growth rate observed under most growth conditions previously examined. Past studies have suggested that this linear relationship represents an optimal resource allocation strategy for each growth rate, independent of any specific nutrient state. Here we investigate protein production strategies in continuous cultures limited for carbon, nitrogen and phosphorus, which differentially impact substrate supply for protein versus nucleic acid metabolism. Unexpectedly, we find that at slow growth rates, Escherichia coli achieves the same protein production rate using three different strategies under the three different nutrient limitations. Under phosphorus (P) limitation, translation is slow due to a particularly low abundance of ribosomes, which are RNA-rich and thus particularly costly for phosphorous-limited cells. Under nitrogen (N) limitation, translation elongation is slowed by processes including ribosome stalling at glutamine codons. Under carbon (C) limitation, translation is slowed by accumulation of inactive ribosomes not bound to messenger RNA. These extra ribosomes enable rapid growth acceleration during nutrient upshift. Thus, bacteria tune ribosome usage across different limiting nutrients to enable balanced nutrient-limited growth while also preparing for future nutrient upshifts.

show abstract

Section: Discussionmentioning

confidence: 92%

Escherichia coli translation strategies differ across carbon, nitrogen and phosphorus limitation conditions

et al. 2018

View full text Add to dashboard Cite

show abstract

“…determined by the relative abundance of active ribosomes in the proteome [24,25]. We remark that the competition between mRNAs for ribosomes is crucial to obtain the exponential growth of ribosomes; increasing transcription rate does not affect the translation rate due to the cancellation in the factor m i / j m j .…”

Section: Model Of Stochastic Gene Expressionmentioning

confidence: 89%

“…The ubiquity of homeostasis suggests that the global machineries of gene expression, RNA polymerases (RNAPs) and ribosomes, should play a central role within the model. Indeed, as we will show later, the exponential growth of cell volume, protein and mRNA number originates from the auto-catalytic nature of ribosomes, the limiting factor in the translational process [24][25][26]. The bounded distributions of concentrations are a result of the fact that ribosomes make all proteins.…”

mentioning

confidence: 89%

“…The most direct evidence is the growth law: the growth rate of cells is proportional to the fraction of ribosomal proteins in the total proteome (with a constant factor depending on the growth condition) [33] both for bacterial cells [24,34] and budding yeast cells [25]. This means a constant fraction of ribosomes are actively translating mRNAs.…”

Section: Model Of Stochastic Gene Expressionmentioning

confidence: 99%

See 1 more Smart Citation

Homeostasis of protein and mRNA concentrations in growing cells

Lin

Amir

2018

Preprint

View full text Add to dashboard Cite

Many experiments show that the concentrations of protein and mRNA fluctuate but on average are constant in growing cells, independent of the genome copy number. However, models of stochastic gene expression often assume constant gene expression rates that are proportional to the gene copy numbers, which are therefore incompatible with experiments. Here, we construct a minimal gene expression model to fill this gap. We show that (1) because the ribosomes translate all proteins, the concentrations of proteins are regulated in an exponentially growing cell volume; (2) the competition between genes for the RNA polymerases makes the gene expression rate independent of the genome number; (3) the fluctuations in ribosome level and cell density can generate a global extrinsic noise in protein concentrations; (4) correlations between mRNA and protein levels can be quantified.Despite the noisy nature of gene expression [1][2][3][4][5][6], various aspects of single cell dynamics, such as volume growth, are effectively deterministic. Recent single-cell measurements show that the growth of cell volumes is often exponential. These include bacteria [7][8][9][10], budding yeast [10][11][12][13][14] and mammalian cells [10,15]. Moreover, the mRNA and protein numbers are on average proportional to the cell volume throughout the cell cycle [16][17][18][19][20]. Therefore, the homeostasis of mRNA concentration and protein concentration is maintained in an exponentially growing cell volume. The exponential growths of mRNA and protein number indicate dynamical transcription and translation rates proportional to the cell volume, and also independent of the genome copy number. However, current gene expression models often assume a fixed cell volume with constant transcription and translation rates [1,5,[21][22][23], which are proportional to the gene copy number. Therefore, fixed cell volume models fail to reveal how cells keep constant mRNA and protein concentrations as the cell volume grows and the genome is replicated.The homeostasis of protein and mRNA concentrations imply that there must be a regulatory mechanism in place to prevent the accumulation of noise over time and to maintain a bounded distribution of concentrations. The goal of this work is to identify such a mechanism by developing a genome-wide coarse-grained model taking into account explicitly cell volume growth. We will consider an idealized cell in which genes are constitutively expressed for simplicity. The ubiquity of homeostasis suggests that the global machineries of gene expression, RNA polymerases (RNAPs) and ribosomes, should play a central role within the model. Indeed, as we will show later, the exponential growth of cell volume, protein and mRNA number originates from the auto-catalytic nature of ribosomes, the limiting factor in the translational process [24][25][26]. The bounded distributions of concentrations are a result of the fact that ribosomes make all proteins. The independence of the mRNA concentration of the genome copy number is a natural resul...

show abstract

“…TFs seem only to complement the action of the global regulation (Berthoumieux et al, 2014, Gerosa et al, 2014, in combination with a few metabolites (Kochanowski et al, 2017). Results in eukaryotes are however lacking (Keren et al, 2014, Metzl-Raz et al, 2017, partly because one has to study a more complex basal regulatory machinery.…”

Section: Introductionmentioning

confidence: 99%

Complex genetic and epigenetic regulation deviates gene expression from a unifying global transcriptional program

Chagoyen

Poyatos

2018

Preprint

View full text Add to dashboard Cite

Environmental or genetic perturbations lead to gene expression changes. While most analyses of these changes emphasize the presence of qualitative differences on just a few genes, we now know that changes are widespread. This large-scale variation has been linked to the exclusive influence of a global transcriptional program determined by the new physiological state of the cell. However, given the sophistication of eukaryotic regulation, we expect to have a complex structure of deviations from the global program. Here, we examine the regulatory landscape that contributes to these deviations. Using data of Saccharomyces cerevisiae expression in different nutrient conditions, we first propose a five-component genome partition as a framework to understand expression variation. In this framework, we recognize invariant genes, whose regulation is dominated by the global program, specific genes, which substantially depart from it, and two additional classes that respond to intermediate regulatory schemes. Whereas the invariant class shows a considerable absence of specific regulation, the rest is enriched by regulation at the level of transcription factors (TFs) and epigenetic modulators. We nevertheless find markedly different strategies in how these classes deviate. On the one hand, there are TFs that act in an exclusive way between partition constituents, and on the other, the action of chromatin modifiers is significantly diverse. The balance between regulatory strategies ultimately modulates the action of the general transcription machinery, and therefore limits the possibility of establishing a single program of expression change at a genomic scale.All rights reserved. No reuse allowed without permission.(which was not peer-reviewed) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity.

show abstract

Principles of cellular resource allocation revealed by condition-dependent proteome profiling

Cited by 27 publications

References 61 publications

Escherichia coli translation strategies differ across carbon, nitrogen and phosphorus limitation conditions

Escherichia coli translation strategies differ across carbon, nitrogen and phosphorus limitation conditions

Homeostasis of protein and mRNA concentrations in growing cells

Complex genetic and epigenetic regulation deviates gene expression from a unifying global transcriptional program

Contact Info

Product

Resources

About