Epigenetics and Multiscale Genomics
- Modesto Orozco (University of Barcelona and Institute for Research in Biomedicine, Spain)
Just a decade ago an invisible wall separated genomics from structural biology. DNA was studied as a mono-dimensional entity whose expression was mysteriously regulated by proteins recognizing short sequences of DNA, without any role of the structure of chromatin in such recognition. Three techniques broke this invisible wall: i) Chipseq (1) which allowed us to map protein binding at the chromatin level, ii) MNaseq (2) which informed on nucleosome positioning and iii) Chromosome Conformation Capture (3C and related; 3) techniques which allowed us to gain information on the overall chromatin arrangement. For a decade now these three families of techniques have provided data opening the possibility to discover the mechanism in which DNA is packed inside the nucleus, how this packing is altered by epigenetic signals and how this is used by the cell to regulate genome activity (4-5). We are now discovering the layers of complexity generated by the three-dimensional structure of DNA when wrapped in the chromatin fibre, and the wall separating it from structural biology is falling, approaching biology to physics.
Experimental high-throughput techniques such as 3C, MNaseq or Chipseq provide huge volumes of noisy data which interpretation requires a solid theoretical framework. This has encouraged the generation of new simulation techniques designed to provide a multi-resolution picture of eukaryotic DNA, from the atomic (Å-scale) to the chromatin (meter-scale) levels. The final goal of these efforts will be to develop a continuum of methodologies able to move from atomistic to coarse grained, mesoscopic and macroscopic levels. Methods should be interconnected, and flexible enough to incorporate experimental restrains and to account for structural changes related to epigenetic modifications (6-7). Reviewing recent advances in this exciting field will be the goal of this workshop.
This workshop aims to bring together scientist working in the study of chromatin at different levels of resolution to foster the integration between the different methodologies to advance in the generation of a complete multiscale platform to describe DNA in its physiological environment. Among others we will discuss on:
• Atomistic methods for DNA simulation. What is the state of the art? What are the scale barriers? How can they link with coarse-grained and mesoscopic methods? What information can they provide on protein-DNA contacts and on nucleosome organization? Can they provide information on the phenotypic changes related to epigenetic changes? How can they interact with experimental techniques?
• Coarse-Grained and Mesoscopic models. What is the state of the art? Which are the accuracy and size limits of these methods? How can they incorporate information on epigenetic variants? Can they treat the intrinsic chromatin polymorphisms? How they should interact with atomistic and macroscopic methods? How can they interact with experimental techniques?
• Macroscopic models. What is the state of the art? Which is the accuracy and resolution of these methods? How can they incorporate experimental information? How can they incorporate information derived from higher resolution models?
• Integrative approaches. What are the most successful approaches for interaction with cell biologists? What are the last generation methods for integrating 3D and 1D genomic information? What are the Last generation multiresolution browsers?
We plan a multidisciplinary meeting, with theoretical groups interested in representing the DNA from first principles, and other relying on experimental information. We aim a meeting where scale will jump ten orders of magnitude and where concerns on the accuracy of force-fields to account for stacking interaction will coexists with concerns on the accuracy of HiC-derived constrains for the determination of global chromatin conformation.
1) Johnson, DS; Mortazavi, A; et al. (2007). "Genome-wide mapping of in vivo protein–DNA interactions". Science. 316: 1497–150
2) Jiang,C.; Pugh,B.F. (2009) “Nucleosome positioning and gene regulation: advances through genomics”. Nat. Rev. Genet., 10: 161-17
3) Dekker, J; Rippe, K; Dekker, M; Kleckner, N (2002). "Capturing chromosome conformation.". Science. 295: 1306–11.
4) Rao, et al. (2014). "A 3D map of the human genome at kilobase resolution reveals principles of chromatin looping". Cell. 159: 1665–1680.
5) Schwartzman, O.; Tanay, A (2015). "Single-cell epigenomics: techniques and emerging applications". Nature Reviews Genetics. 16: 716–726
6) Dans,P.; Walther,J.; Gómez,H.; Orozco,M.(2016) “Multiscale simulation of DNA”. Current Opin. Struct. Biol., 37: 29-45
7) Grigoryec,G.; Bascom,M.; Schubert,C.; Woodcock,C.; Schlich,T. (2016) “Loopging of zigzag nucleosome chains in metaphase chromosomes”. Proc. Natl. Acad. Sci. USA, 113: 1238-43.
8) F.Le Dily, F.Serra, M.A. Marti-Renom. (2017) “3D modeling of chromatin structure: is there a way to integrate and reconcile single cell and population experimental data?”. WIRES Comp.Mol.Sci., DOI 10.1002/wcms.1308