CE45 - Mathématique, informatique, automatique, traitement du signal pour répondre aux défis de la biologie et de la santé

Quantitative modeling of the 3D dynamical organization of chromosomes – 3DynOrg

3DynOrg : Quantitative modeling of the 3D dynamical organization of chromosomes

Many biological processes require proper 3D organization and dynamics to function normally. The regulation of these properties mainly originates from known molecular mechanisms. However, how such microscopic actions are coupled to collectively generate large-scale functions remains a major challenge in biology. We are addressing this question in the context of the 3D dynamical, multi-scale organization of chromosomes, which represents one of the major challenge faced in recent years by biology.

Main objectives

We will investigate the unexplored, non-stationary dynamics of such <br />topologically-constraint, long heteropolymers. To tackle the behaviors of these long polymeric chains over long time periods, we will design robust and efficient, modular simulation methods. We will develop a complete framework for chromosome folding by separately and systematically studying the characteristics of three fundamental mechanisms driving it at different scales: interaction with the nuclear membrane, (micro)phase-segregation of inactive/active genomic regions, and polymer loop extrusion by active translocating motors. We will recombine these approaches into a unified understanding where the complex, hierarchical chromosome organization in space and time emerges from the interplay between these different processes. In close collaboration with experimentalists, our theoretical findings will be contextualized and applied to several outstanding problems in the emerging and booming field of 3D genomics. Our work will break new grounds both in fundamental and physical biology. On the fundamental side, it will establish a new framework to understand how chromosomes control their organization <br />and dynamics through the cooperation of basic molecular processes. On the physical side, it will bring new simulation tools and theories to understand the behaviors of large-scale multi-agent systems and will open new paradigms for the emergence of original collective effects from short-range interactions or active translocations.

Our methodology is mainly based on the development of polymer models adapted to the questions under study and of advanced numerical simulations. For polymer modeling, we often used semi-flexible, self-avoiding polymers as null models that we decorate with specific passive or active interactions. Simulations of these models are performed either using advanced molecular dynamics software either using our homemade lattice, kinetic Monte-Carlo model that is very efficient and allow modularity.

1) Using extensive numerical simulations, we systematically investigated the confinement of semi-flexible polymers inside an elastic membrane. We observe a wide variety of phases coupling chains & membrane buckling transitions. We contextualize this framework to chromatin organization during cricket spermatogenesis.
2) We developed a polymer model describing the full genome organization in the plant Arabidopsis thaliana. In particular, we account for epigenetic-driven interactions and showed the important role of heterochromatin and nucleolar-associated domains in shaping nuclear architecture (Di Stefano et al, bioRxiv, 2020).
3) We developed a theoretical framework to investigate homolog somatic pairing in Drosophila. Using polymer modeling and live-imaging (in collaboration with H. Garcia (UC Berkeley) & J. Bateman (Bowdouin Univ)), we showed that a phase separation driven by specific homologous buttons may drive the time-dependent pairing observed during embryogenesis (Child et al, bioRxiv, 2020).
4) Using heteropolymer models, we provided a comprehensive study of chromosome dynamics. We showed that the hierarchical folding of the genome leads to strong heterogeneity in chromatin motion. Using toy models, we investigated the precise contributions of the different layers of chromosome organization.

The project is ongoing so perspectives will be discussed at the final stage.

1. M. Tortora, H. Salari & D. Jost, Chromosome dynamics during interphase: a biophysical perspective, Curr. Opin. Genes Dev. 61: 37-43 (2020).
2. S.K. Ghosh & D. Jost, Genome organization via loop extrusion, insights from polymer physics models, Brief. Func. Genom. 19: 119-127 (2020).
3. M. Di Stefano, J. Paulsen, D. Jost & M.A. Marti-Renom, 4D Nucleome modeling, Curr. Opin. Genes Dev., in submission.
4. M. Di Stefano, H.-W. Nutzmann, M. A. Marti-Renom & D. Jost, Polymer modelling unveils the roles of heterochromatin and nucleolar organizing regions in shaping 3D genome organization in Arabidopsis thaliana, bioRxiv
2020.05.15.098392, under revision.
5. M. Child, J.R. Bateman*, A. Jahangiri, A. Reimer, N.C. Lammers, N. Sabouni, D. Villamarin, G.C. McKenzie-Smith, J.E. Johnson, D. Jost * & H.G. Garcia*, Live imaging and biophysical modeling support a button-based mechanism of somatic homolog pairing in Drosophila, bioRxiv 2020.08.30.265108, in submission. (* joint corresponding authors)
6. D. Jost, Polymer modeling of epigenome folding: application to Drosophila, in «Hi-C data analysis: Methods and Protocols« in the «Methods in Molecular Biology« Series (Springer Nature, Editors F. Ferrari & S. Bicciato) (2020)

Many biological processes require proper 3D organization and dynamics of the underlying biomolecules to function normally. The regulation of these structural and dynamical properties mainly originates from known molecular mechanisms. However, how such microscopic actions are coupled to collectively generate large-scale functions remains a major challenge in biology.
We will bridge this gap through the quantitative modeling of the emergence of the 3D dynamical, multi-scale organization of chromosomes, which represents one of the major challenge faced in recent years by biology. We will investigate the unexplored, non-stationary dynamics of such topologically-constraint, long heteropolymers. To tackle the behaviors of these long polymeric chains over long time periods, we will design robust and efficient, modular simulation methods. We will develop a complete framework for chromosome folding by separately and systematically studying the characteristics of three fundamental mechanisms driving it at different scales: interaction with the nuclear membrane, (micro)phase-segregation of inactive/active genomic regions, and polymer loop extrusion by active translocating motors. We will recombine these approaches into a unified understanding where the complex, hierarchical chromosome organization in space and time emerges from the interplay between these different processes. In close collaboration with experimentalists, our theoretical findings will be contextualized and applied to several outstanding problems in the emerging and booming field of 3D genomics.
Our work will break new grounds both in fundamental and physical biology. On the fundamental side, it will establish a new framework to understand how chromosomes control their organization and dynamics through the cooperation of basic molecular processes. On the theoretical side, it will bring new simulation tools and theories to understand the behaviors of large-scale multi-agent systems and will open new paradigms for the emergence of original collective effects from short-range interactions or active translocations.

Project coordinator

Monsieur Daniel Jost (LABORATOIRE DE BIOLOGIE ET MODELISATION DE LA CELLULE)

The author of this summary is the project coordinator, who is responsible for the content of this summary. The ANR declines any responsibility as for its contents.

Partner

LBMC LABORATOIRE DE BIOLOGIE ET MODELISATION DE LA CELLULE

Help of the ANR 284,531 euros
Beginning and duration of the scientific project: February 2019 - 48 Months

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