Ref HAL: inserm-02952457_v1
PMID 32958811
DOI: 10.1038/s41467-020-18455-z
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Résumé:

Genetic programs operating in a history-dependent fashion are ubiquitous in nature and govern sophisticated processes such as development and differentiation. The ability to systematically and predictably encode such programs would advance the engineering of synthetic organisms and ecosystems with rich signal processing abilities. Here we implement robust, scalable history-dependent programs by distributing the computational labor across a cellular population. Our design is based on standardized recombinase-driven DNA scaffolds expressing different genes according to the order of occurrence of inputs. These multicellular computing systems are highly modular, do not require cell-cell communication channels, and any program can be built by differential composition of strains containing well-characterized logic scaffolds. We developed automated workflows that researchers can use to streamline program design and optimization. We anticipate that the history-dependent programs presented here will support many applications using cellular populations for material engineering, biomanufacturing and healthcare.

Ref HAL: hal-01938456_v1
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Many theoretical works have attempted to coarse grain gene expression at the level of transcription and translation via frameworks based on exclusion processes. Usually in these models the three-dimensional conformation of the substrates (DNA and mRNA) is neglected, and particles move on a static unidimensional lattice in contact to an infinite reservoir. In this work we generalise the paradigmatic exclusion process and study the transport of particles along a unidimensional polymer-like flexible lattice immersed in a three-dimensional particle reservoir. We study the recycling of particles in the reservoir, how the transport is influenced by the conformation of the lattice and, in turn, how particle density dictates the structure of the polymer.

Ref HAL: hal-01938431_v1
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One of the greatest challenges in biophysical models of translation is to identify coding sequence features that affect the rate of translation and therefore the overall protein production in the cell. We propose an analytic method to solve a translation model based on the inhomogeneous totally asymmetric simple exclusion process, which allows us to unveil simple design principles of nucleotide sequences determining protein production rates. Our solution shows an excellent agreement when compared to numerical genome-wide simulations of S. cerevisiae transcript sequences and predicts that the first 10 codons, which is the ribosome footprint length on the mRNA, together with the value of the initiation rate, are the main determinants of protein production rate under physiological conditions. Finally, we interpret the obtained analytic results based on the evolutionary role of the codons’ choice for regulating translation rates and ribosome densities.

Ref HAL: hal-01938405_v1
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In this talk I will present our understanding on the relation between codon and ribosome usage, and its link to bacterial growth rate.

Ref HAL: hal-01938095_v1
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Proteins are the basis of cellular functions, yet key parameters regulating protein synthesis remain elusive. Understanding the fine mechanisms of regulation is a major goal of molecular and systems biology, and this knowledge will support many synthetic biology applications.We have the ambitious goal of providing a biophysical modelling framework of one of the last steps in protein synthesis, namely mRNA translation. Our work focuses on translation initiation and elongation, which relative role is highly debated in the literature: is the ribosome recruitment or the codon bias determining the expression of a gene? We explain how the transcript efficiency can be dictated by ribosome abundances, codon usage and transcript length.We propose analytical and simulation methods to investigate translation models based on an inhomogeneous exclusion process, the prototypical non-equilibrium traffic model in one dimension. We show that the first codons, together with the value of the initiation rate, are the main determinants of protein production. Finally, we interpret the obtained analytical results based on the evolutionary role of codons’ choice for regulating translation rates and ribosome usage.

Ref HAL: hal-01935528_v1
Exporter : BibTex | endNote
Résumé:

Proteins are the basis of cellular functions, yet key parameters regulating protein synthesis remain elusive. Understanding the fine mechanisms of regulation is a major goal of molecular and systems biology, and this knowledge will support many synthetic biology applications.We have the ambitious goal of providing a biophysical modelling framework of one of the last steps in protein synthesis, namely mRNA translation. Our work focuses on translation initiation and elongation, which relative role is highly debated in the literature: is the ribosome recruitment or the codon bias determining the expression of a gene? We explain how the transcript efficiency can be dictated by ribosome abundances, codon usage and transcript length.We propose analytical and simulation methods to investigate translation models based on an inhomogeneous exclusion process, the prototypical non-equilibrium traffic model in one dimension. We show that the first codons, together with the value of the initiation rate, are the main determinants of protein production. Finally, we interpret the obtained analytical results based on the evolutionary role of codons' choice for regulating translation rates and ribosome usage.

Ref HAL: hal-01743450_v1
Ref Arxiv: 1803.08110
DOI: 10.1103/PhysRevE.99.052409
WoS: WOS:000469026300012
Ref. & Cit.: NASA ADS
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2 Citations
Résumé:

Many theoretical works have attempted to coarse grain gene expression at the level of transcription and translation via frameworks based on exclusion processes. Usually in these models the three-dimensional conformation of the substrates (DNA and mRNA) is neglected, and particles move on a static unidimensional lattice in contact to an infinite reservoir. In this work we generalise the paradigmatic exclusion process and study the transport of particles along a unidimensional polymer-like flexible lattice immersed in a three-dimensional particle reservoir. We study the recycling of particles in the reservoir, how the transport is influenced by the conformation of the lattice and, in turn, how particle density dictates the structure of the polymer.

Commentaires: 5 pages, 4 figures