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Compte rendu des activités autour de la modélisation physico-mathématique du transport moléculaire intracellulaire

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Resumé des activités de l'equipe SCPN sur la modélisation de la ségrégation et du positionnement du génome bactérie

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Translation of messenger RNA (mRNA) leads to the production of proteins and is the last step of gene expression in cells. The dysregulation of translation can lead to all illnesses linked to the dysregulation of protein production, like cancer and neurodegenerative diseases.About ten years ago, a ribosomal density mapping strategy (Ribo-seq) was developed. The time is therefore ripe to apply theoretical physicsmethods to study translation. We model the movement of ribosomes on mRNA using the Totally Asymmetric Simple Exclusion Process (TASEP) which is an out of equilibrium one dimensional directed transport model. With Monte Carlo simulations and a mean field approach, we propose a way to calculate the speed of ribosomes from experimental data. Moreover, we provide preliminary results concerning the correlation between the speed of ribosomes and the occurrence rate of codons (RSCU).

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The DNA shows a high degree of spatial and dynamical organization over a broad range of length scales. It interacts with different populations of proteins and can form protein-DNA complexes that underlie various biological processes, including chromosome segregation. A prominent example is the large ParB-DNA complex, an essential component of a widely spread mechanism for DNA segregation in bacteria. Recent studies suggest that DNA-bound ParB proteins interact with each other and condense into large clusters with multiple extruding DNA-loops.In my talk, I present the Looping and Clustering model [1], a simple statistical physics approach to describe how proteins assemble into a protein-DNA cluster with multiple loops. Our analytic model predicts binding profiles of ParB proteins in good agreement with data from high precision ChIP-sequencing – a biochemical technique to analyze the interaction between DNA and proteins at the level of the genome. The Looping and Clustering framework provides a quantitative tool that could be exploited to interpret further experimental results of ParB-like protein complexes and gain some new insights into the organization of DNA.

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PMID 30446599
DOI: 10.15252/msb.20188516
WoS: 000451579500003
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14 Citations
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Chromosome and plasmid segregation in bacteria are mostly driven by ParABS systems. These DNA partitioning machineries rely on large nucleoprotein complexes assembled on centromere sites (parS). However, the mechanism of how a few parS-bound ParB proteins nucleate the formation of highly concentrated ParB clusters remains unclear despite several proposed physico-mathematical models. We discriminated between these different models by varying some key parameters in vivo using the plasmid F partition system. We found that ‘Nucleation & caging’ is the only coherent model recapitulating in vivo data. We also showed that the stochastic self-assembly of partition complexes (i) does not directly involve ParA, (ii) results in a dynamic structure of discrete size independent of ParB concentration, and (iii) is not perturbed by active transcription but is by protein complexes. We refined the ‘Nucleation & Caging’ model and successfully applied it to the chromosomally-encoded Par system of Vibrio cholerae, indicating that this stochastic self-assembly mechanism is widely conserved from plasmids to chromosomes.

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We model the ParABS system, which is a bacterial DNA Segregation Apparatus.

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Ref Arxiv: 1707.01373
DOI: 10.1088/1367-2630/aaad39
WoS: 000428767700002
Ref. & Cit.: NASA ADS
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4 Citations
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The bacterial genome is organized in a structure called the nucleoid by a variety of associated proteins. These proteins can form complexes on DNA that play a central role in various biological processes, including chromosome segregation. A prominent example is the large ParB-DNA complex, which forms an essential component of the segregation machinery in many bacteria. ChIP-Seq experiments show that ParB proteins localize around centromere-like parS sites on the DNA to which ParB binds specifically, and spreads from there over large sections of the chromosome. Recent theoretical and experimental studies suggest that DNA-bound ParB proteins can interact with each other to condense into a coherent 3D complex on the DNA. However, the structural organization of this protein-DNA complex remains unclear, and a predictive quantitative theory for the distribution of ParB proteins on DNA is lacking. Here, we propose the Looping and Clustering (LC) model, which employs a statistical physics approach to describe protein-DNA complexes. The LC model accounts for the extrusion of DNA loops from a cluster of interacting DNA-bound proteins. Conceptually, the structure of the protein-DNA complex is determined by a competition between attractive protein interactions and the configurational and loop entropy of this protein-DNA cluster. Indeed, we show that the protein interaction strength determines the "tightness" of the loopy protein-DNA complex. With this approach we consider the genomic organization of such a protein-DNA cluster around a single high-affinity binding site. Thus, our model provides a theoretical framework to quantitatively compute the binding profiles of ParB-like proteins around a cognate (parS) binding site.

Commentaires: 14 pages, 7 figures