Integrating genomics with hierarchical physical models of DNA and chromosomes
CECAM-FR-RA, Centre Blaise Pascal, ENS Lyon, France
We propose to focus a multidisciplinary CECAM workshop on the analysis and the modeling of the 3D organisation of the genome. In particular, we want explore, if it is possible to predict genome folding as a function of the DNA sequence and epigenetic state by adapting models and tools developed in computational soft matter physics to study structure formation in polymer systems, and whether this will enable us to understand how these genomes are regulated. The workshop will debate whether for systems of this enormous complexity, the “bottom up” ab initio approaches that have proven so successful in the physical sciences can every prove as useful in biology. The specific topics will be:
1. The generic, sequence- and species averaged folding of chromosomes
a. Overview over experimental FISH and HiC results of the 3d structure
i. Evidence for universal, generic behavior?
ii. What do experimentalists mean by “topological domains” and is there anything “topological” about it?
b. The physics of topological constraint induced crumpling
i. Lattice trees, space-filling curves, crumpled globules.
c. Generic polymer models of crumpled polymers
i. Mapping to chromatin fibers
ii. Computational performance of bead-spring and lattice models
2. The specific sequence- and epigenetic state-dependent folding of chromosomes
a. Hetero- vs. Euchromatin
b. Epigenetic mechanisms for the regulation of gene activity
c. Evidence for a limited number of epigenetic states of the chromatin fiber
d. Correlation between epigenetic and topological domains
3. Restraint-based modeling of the 3d folding
a. Definition of the scoring function
b. Optimization methods
c. Interpretation of results and, in particular, of the predicted ensembles of 3d structures
4. Modeling epigenetic regulation of chromosome folding
a. Limits for the applicability of generic coarse-grain polymer models for the chromatin fiber (the current state of the 30nm chromatin fiber etc.)
b. Chromatin Looping
c. “Topological” domains: microphase separation of epigenetic domains?
d. Topological constraints and structure formation: are there alternatives to massive simulations? Or: Can one include topological constraints into self-consistent field theory?
e. How to parameterize (co-)polymer models chromatin fibers with epigenetically controlled interactions?
f. Hierarchical modelling of DNA - from ab initio quantum mechanics to atomistic models, from the atomistic to coarse-grained length-scales, to the statistical mechanics of DNA supercoiling of the genome
5. The influence of replication and transcription activity on the chromosome structure
(Coupling between replication, transcription and the chromosome structure ?)
6. Bioinformatics and systems biology of gene regulation in prokaryotes and eukaryotes - what is has it achieved, and what is still missing?
Ralf Everaers (École Normale Supérieure de Lyon) - Organiser
Cedric Vaillant (Laboratoire de Physique, ENS Lyon) - Organiser
Sarah Harris (University of Leeds) - Organiser