Sensitivity of mRNA Translation

Poker, Gilad; Margaliot, Michael; Tuller, Tamir

doi:10.1038/srep12795

Cited by 35 publications

(37 citation statements)

References 32 publications

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“…Each dot in Figure 4E correspond to one codon, and includes the correlation between its frequency and protein levels in the library L2-41C (x-axis) vs. the correlation between its frequency and protein levels in the library L42-81C (y-axis). Our study differentiates the nature and strength of the effect of synonymous mutations in different parts of the transcript/ORF on protein levels, and may be used to guide the design of synthetic genes 52 . The reported results support the notion that the term "optimal codons" (see, for example, 27,53 ), which describes the preferred codon for each amino acid in a certain organism, should be fine tuned; optimal codons are context dependent and may vary among different parts of the ORF.…”

Section: The Direction Of the Effect Of Synonymous Codons And Silent mentioning

confidence: 99%

Rationally designed, heterologousS. cerevisiaetranscripts expose novel expression determinants

et al. 2015

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Deducing generic causal relations between RNA transcript features and protein expression profiles from endogenous gene expression data remains a major unsolved problem in biology. The analysis of gene expression from heterologous genes contributes significantly to solving this problem, but has been heavily biased toward the study of the effect of 5' transcript regions and to prokaryotes. Here, we employ a synthetic biology driven approach that systematically differentiates the effect of different regions of the transcript on gene expression up to 240 nucleotides into the ORF. This enabled us to discover new causal effects between features in previously unexplored regions of transcripts, and gene expression in natural regimes. We rationally designed, constructed, and analyzed 383 gene variants of the viral HRSVgp04 gene ORF, with multiple synonymous mutations at key positions along the transcript in the eukaryote S. cerevisiae. Our results show that a few silent mutations at the 5'UTR can have a dramatic effect of up to 15 fold change on protein levels, and that even synonymous mutations in positions more than 120 nucleotides downstream from the ORF 5'end can modulate protein levels up to 160%-300%. We demonstrate that the correlation between protein levels and folding energy increases with the significance of the level of selection of the latter in endogenous genes, reinforcing the notion that selection for folding strength in different parts of the ORF is related to translation regulation. Our measured protein abundance correlates notably(correlation up to r = 0.62 (p=0.0013)) with mean relative codon decoding times, based on ribosomal densities (Ribo-Seq) in endogenous genes, supporting the conjecture that translation elongation and adaptation to the tRNA pool can modify protein levels in a causal/direct manner. This report provides an improved understanding of transcript evolution, design principles of gene expression regulation, and suggests simple rules for engineering synthetic gene expression in eukaryotes.

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Section: The Direction Of the Effect Of Synonymous Codons And Silent mentioning

confidence: 99%

Rationally designed, heterologousS. cerevisiaetranscripts expose novel expression determinants

et al. 2015

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“…This is the mean-field approximation of the unidirectional TASEP without Langmuir kinetics (see, e.g., [52, section 4.9.7] and [6, p. R345]). Recently, the RFM has been studied extensively using tools from systems and control theory [36], [71], [37], [38], [35], [44], [45], [47], [70]. The analysis is motivated by implications to many important biological questions.…”

Section: Introductionmentioning

confidence: 99%

A deterministic mathematical model for bidirectional excluded flow with Langmuir kinetics

2017

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In many important cellular processes, including mRNA translation, gene transcription, phosphotransfer, and intracellular transport, biological “particles” move along some kind of “tracks”. The motion of these particles can be modeled as a one-dimensional movement along an ordered sequence of sites. The biological particles (e.g., ribosomes or RNAPs) have volume and cannot surpass one another. In some cases, there is a preferred direction of movement along the track, but in general the movement may be bidirectional, and furthermore the particles may attach or detach from various regions along the tracks. We derive a new deterministic mathematical model for such transport phenomena that may be interpreted as a dynamic mean-field approximation of an important model from mechanical statistics called the asymmetric simple exclusion process (ASEP) with Langmuir kinetics. Using tools from the theory of monotone dynamical systems and contraction theory we show that the model admits a unique steady-state, and that every solution converges to this steady-state. Furthermore, we show that the model entrains (or phase locks) to periodic excitations in any of its forward, backward, attachment, or detachment rates. We demonstrate an application of this phenomenological transport model for analyzing ribosome drop off in mRNA translation.

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“…for all t ≥ 0, all x ∈ Ω. Let γ(t) be the unique, attracting, T -periodic orbit of (30) in Ω. Suppose also that for the unforced dynamics, i.e.ẋ = F (x, 0), there exists a locally stable equilibrium point e ∈ Ω, and without loss of generality, that e = 0.…”

Section: An Lti Approximationmentioning

confidence: 99%

Approximating periodic trajectories of contractive systems

Margaliot

Coogan

2017

2017 IEEE 56th Annual Conference on Decision and Control (CDC)

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We consider contractive systems whose trajectories evolve on a compact and convex state-space. It is well-known that if the time-varying vector field of the system is periodic then the system admits a unique globally asymptotically stable periodic solution. Obtaining explicit information on this periodic solution and its dependence on various parameters is important both theoretically and in numerous applications. We develop an approach for approximating such a periodic trajectory using the periodic trajectory of a simpler system (e.g. an LTI system). Our approximation includes an error bound that is based on the input-to-state stability property of contractive systems. We show that in some cases this error bound can be computed explicitly. We also use the bound to derive a new theoretical result, namely, that a contractive system with an additive periodic input behaves like a low pass filter. We demonstrate our results using several examples from systems biology. * M. Margaliot is with the School of Electrical Engineering and the

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Sensitivity of mRNA Translation

Cited by 35 publications

References 32 publications

Rationally designed, heterologousS. cerevisiaetranscripts expose novel expression determinants

Rationally designed, heterologousS. cerevisiaetranscripts expose novel expression determinants

A deterministic mathematical model for bidirectional excluded flow with Langmuir kinetics

Approximating periodic trajectories of contractive systems

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