Multiscale Modeling and Experimental Approaches to Genome Organization
Ecole de Physique, Les Houches (F)
The site of the school is open from Sunday April 2, 15h to Friday April 7, 16h. People who want to arrive earlier / leave later need to find accommodation in the Les Houches / Chamonix area. Look for hotels, pensions, and also AirBnB.
For the travel info see https://houches.univ-grenoble-alpes.fr/en/practical-information.
Transport from Geneva to Les Houches: please organize yourself; transport from the village to the school; we might organize joint transport if there is enough interest. Note that the school does not open before Sunday, 15h.
Accommodation and food: 400 Euro to be paid on-site (cash or credit card).
Advances in high-speed computational platforms and innovative algorithms are opening opportunities for multiscale modeling in biology as never before. While there are general methods, the most successful approaches are tailored and tightly connected with the application at hand. One such application area where a variety of models and methods --- from atomistic to polymer levels --- are critically needed to bridge experimental data involves the genome material, or the chromatin fiber in higher organisms.
Understanding and interpreting the structure and function of the genomic material in the live eukaryotic cell has been an enduring challenge in modern science (Kornberg&Thomas 1974, Finch et al. 1977, Wolffe 1998, vanHolde&Zlatanova 2007). As our appreciation for the diversity and flexibility of DNA on the dodecamer level has deepened (e.g., Levitt 1978), its large-scale bending and coiling around histone proteins to form the chromosomal material in higher organisms has posed many structural and mechanistic questions (Felsenfeld 1996, Felsenfeld&Groudine 2003, Becker&Everaers 2009}. The genomic information in the DNA is packaged in a hierarchy of levels, from the nucleosome to condensed chromatin fibers to chromosomes and chromosomal territories. Thus, profound questions regarding DNA geometry, topology, and function span from the single nucleosome/base-pair level to condensed chromosomal arrangements on the mega-basepair level in the metaphase cell cycle. Not only do we lack an understanding of the structure of the chromatin fiber and chromosomosal arrangements; we know little of how structural transformations occur. These transitions are tightly controlled by a host of proteins, which can directly bind to the chromatin fiber or induce chemical modifications of DNA and histones. These changes profoundly influence the global organization of the chromatin fiber and in turn affect DNA accessibility by the genome processing machinery. More specifically, transitions involving the nucleosome, fiber, and chromosome levels alter chromatin states from/to open, transcriptionally active to/from closed, transcriptionally silent forms and thereby affect a wide range of genome functions from cell differentiation to replication and transcription. Because these structures and transitions also impact human disease, notably many cancer (Tiwari et al. 2008, Gordon et al. 2015, Rafique et al. 2015, Vallot et al. 2015, deDieuleveult et al. 2016), a better understanding of these processes also has strong translational ramifications on human health via epigenome-based therapeutics.
Exciting recent advances in instrumentation are providing important information into these puzzles from X-ray crystallography, Cryo-electron microscopy, in-vitro biochemistry (e.g., Grigoryev et al. 2015), single-nucleosome resolution nanoscopy (Ricci et al. 2015), single-nucleosome fluorescence (Böhm et al. 2011), and genome-wide association data (Lieberman-Aiden et al. 2009, Sanborn et al. 2015 In tandem, in silico modeling from atomistic DNA (e.g. Pasi 2014) to atomic nucleosomes to coarse-grained chromatin fibers to polymer models of chromosomes (e.g., Grigoryev et al. 2015, Beard&Schlick 2001, Ehrlich et al. 97, Wocjan et al. 2009, Erler et al. 2014, Arneodo et al. 2011, Jost et al. 2014, Rosa&Everaers 2008, Benedetti et al. 2014, Collepardo-Guevara et al. 2014 & 2015) is adding insights to help bridge experimental data (Meyer et al. 2011, Ozer et al. 2015).
After an intense debate on “the” structure of the chromatin fiber (vanHolde&Zlatanova 2007, Maeshima et al. 2010) it is becoming clear that chromatin is polymorphic and its structure dependent on many internal and external parameters such as the linker length, linker histone presence and type, divalent ions, etc. (Schlick et al. 2012), discrete states are also being recognized at different cell stages and positions (e.g., Eagen et al. 2015). This behavior poses an extreme challenge to in silico modeling in that it is necessary to systematically and possibly concurrently (Potestio et al. 2014, Zavadlav et al. 2015) link descriptions on different scales.
Much progress has been and continues to be made in our understanding of chromatin organization on the disparate length scales mentioned above. We seek to address two challenges: (i) the bridging between modeling and experimentation on the nucleosome and fiber levels with genome studies on the kilo-base level and (ii) the systematic linking of models describing (parts of) the chromatin fiber on different scales.
Our workshop seeks to bring together multidisciplinary scientists to address these multiscale challenges, from the level of DNA interacting with histones via the local organization of the chromatin fiber to the folding of chromosomes in the cell, from both experimental and modeling perspectives. We hope to create an atmosphere where new ideas from different fields are generated to advance studies of the hierarchical structure of chromatin and the functional implication of these levels and rearrangements on human disease. These advances of ideas and methods for addressing the wide range of spatial and temporal scales associated with chromatin and chromosomes will be accomplished by bringing together broad-minded scientists from different perspectives to discuss the state-of-the-art and ways to advance the field. We plan to feature both regular and overview presentations that will aim to provide background to a multidisciplinary audience and set the stage for discussion sessions, which will address the current gaps. We will also hold poster sessions to encourage interactions among the scientists and enable young researchers to engage in the research. The topics to be presented and discussed are:
1) The dynamic structure of the nucleosome --- approaches from molecular and coarse-grained modeling, atomic-resolution structural analysis and in-solution biophysical techniques --- challenges and approaches;
2) The organization of the chromatin fiber as a function of internal and external parameters (linker DNA length and variations, linker histone concentration, salt environment, etc.) --- merging experiment and theory;
3) The folding of the chromatin chain into chromosomes, connecting modeling with experimental biophysics and biochemistry (e.g., proximity ligation, microscopy) --- merging genome-wide association data measurements with polymer and fiber modeling; and
4) Novel experimental and computational approaches to multi-scale modeling of chromatin architecture --- challenges and approaches.
We also plan to hold several open discussion sessions as well as a Perspectives session at the end to brainstorm about advancing current gaps and possibly forming a working group for future studies. A perspective article will be written by the organizers from the discussion session for publication in an appropriate journal. We will also consider publishing a special volume in Biophysical Journal (T.S. is Associate Editor of the Nucleic Acids and Genome Biophysics Section) from the meeting with articles by invited speakers, edited by the organizing committee. Both the Perspectives report and special volume should be of wide interest. We hope that the workshop will stimulate new techniques for modeling and new collaborations between experimentalist and modelers and hence increase the application scope of biophysical modeling to the community at large.
Ralf Everaers (École Normale Supérieure de Lyon) - Organiser & speaker
Jörg Langowski (Division Biophysics of Macromolecules, German Cancer Research Center (DKFZ), Heidelberg) - Organiser & speaker
Andrzej Stasiak (Center for Integrative Genomics, University of Lausanne) - Organiser & speaker
Tamar Schlick (New York University) - Organiser & speaker