Chromatin Modeling: Integrating Mathematics, Physics, and Computation for Advances in Biology and Medicine

Scientific Background

Advances in high-speed computational platforms and innovative algorithms are opening op- portunities for modeling in biology as never before. In turn, these advances are driving biology and medicine forward, as clearly seen during the Covid-19 pandemic, where basic science of RNA and RNA viruses has helped develop the mRNA-based vaccines. While there are many general methods that can be applied widely like linear algebra routines and fast summation algorithms, the most successful approaches are tailored and tightly connected with both the application at hand and the computing platform. Genome organization is a prominent area where a variety of models and methods — from atomistic to polymer levels — is critically needed to bridge experi- mental data. Genome organization refers to the folding of the genome material, or the chromatin fiber that makes up chromosomes, in the cell nucleus of higher organisms.

Fundamental genome packaging in eukaryotes—and hence regulation of life’s essential pro- cesses like gene expression, DNA repair, and cell differentiation—is determined by the struc- ture and interactions associated with the chromatin fiber—a multiscale nucleoprotein complex of tightly packed nucleosomes connected by linker DNAs, like yarn around many spools. Yet chromatin structure and epigenetic mechanisms remain elusive despite decades of research.

As our appreciation for the diversity and flexibility of DNA on the base-pair level has deepened, its large-scale bending and coiling around histone proteins to form the chromosomal material in higher organisms has posed many structural and mechanistic questions. 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, and disruption of epige- netic mechanisms plays a key role in driving initiation and progression of most human cancers, 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, single-nucleosome resolution nanoscopy, single-nucleosome fluorescence, electron tomography, and genome-wide con- tact data. In tandem, in silico modeling from atomic nucleosomes to coarse-grained chromatin fibers to polymer models of chromosomes underscore the polymorphic nature of chromatin in vivo with enhanced bridging via hierarchical or stacked loops,

While a key question over the past decade has been the detailed structure of the compact (long termed “30-nm”) chromatin fiber — whether zigzag, solenoid, or other, — intensely debated new questions concern phase transitions of disordered fibers. Though it is becoming clear that chromatin structure is polymorphic and dependent on many internal and external parameters such as the DNA linker length, linker histone presence and type, divalent ions, etc., discrete states are also being recognized at different cell stages and positions. Identifying these states, interpreting their transitions and functions, and relating epigenetic marks to global chromatin architecture and disease progression form intense current areas of research, as new models are being proposed to explain the data.


Workshop Goals

Though much progress has been made and continues in our understanding of chromatin organization on the disparate length scales, a bridging between modeling and experimentation on the nucleosome and fiber levels with genome studies on the kilo-base level is lacking. New tailored mul- tiscale computational approaches are needed to help interpret the rising volume of experimental data, especially those coming from genome-wide contact data. In addition, many mathemati- cians and physicists are working on relevant problems but there is a gap in resolution between the mathematical biology community which has developed various coarse-graining approaches for chromatin on the fiber bur not chromosome level and the mathematical physics community which studies scaling behavior on the order of chromosomes but cannot incorporate crucial physical parameters on the fiber level. Since important biological applications require an integration from the base-pair level to chromosome and genome wide scales, it is essential that these communities open collaborative approaches between them, as well as interact with the experimental chromatin and medical scientists.

Our program aims to bring these scientists together to discuss the current state-of-the-art in chromatin modeling, identify future challenges, and follow them with innovative multiscale, integrative approaches.

These multidisciplinary scientists will thus 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 hier- archical structure of chromatin and the functional implication of these levels and rearrangements on human disease. Thus, the development of coarse-grained and multiscale models can serve as an exemplary, high-impact test case for multiscale model development.

These advances of ideas and methods for addressing the wide range of spatial and temporal scales associated with the chromatin fiber 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 a conference during the thematic program of two weeks, as well include a few long-time visitors to work together in more detail on these important problems. We will hold sessions for young scientists to encourage new research directions. We will also invite a large number of women and minorities in all activities.

Discussion Topics

The topics to be presented and discussed are:

  • The dynamic structure of the nucleosome and associated transitions — approaches from molecular and coarse-grained modeling, atomic-resolution structural analysis and in-solution biophysical techniques — challenges and approaches;
  • 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;
  • The folding of the chromatin chain into chromosomes, chromosome topology (knotting), connecting modeling with experimental biophysics and biochemistry (e.g., proximity liga- tion, microscopy) — merging genome-wide association data measurements with polymer and fiber modeling; and
  • Novel computational approaches to multiscale modeling of chromatin architecture — chal- lenges and approaches.

Dates of the core workshop: March 4 - 8, 2024


The three organizers are active researchers in the chromatin and polymer physics fields who approach problems on a broad range of modeling tools and some experimentation. They also closely collaborate extensively with other modelers and experimentalists, and their areas of expertise are complementary.

March 4, 2024
10:00 — 11:00
Registration & Welcome
11:00 — 11:35
12:10 — 12:45
12:45 — 14:00
Lunch Break
14:35 — 15:10
15:45 — 16:15
Discussion and Coffee Break
March 5, 2024
11:10 — 11:30
Coffee Break
11:30 — 12:05
Maria Pia Cosma (Center for Genomic Regulation, Barcelona)
Integrating imaging and genomic approaches to model 3D genome structure
12:40 — 14:00
Lunch Break
15:10 — 15:30
Coffee Break
15:30 — 16:05
16:05 — 16:40
March 6, 2024
09:00 — 13:00
On your own sightseeing / Collaborative discussions at ESI
13:00 — 13:35
14:10 — 14:45
Vladimir Teif (U of Essex)
Nucleosome repositioning in cancer
14:45 — 15:00
Coffee Break
15:00 — 15:35
March 7, 2024
10:35 — 11:10
11:10 — 11:30
Coffee Break
11:30 — 12:05
12:05 — 12:40
Anton Goloborodko (IMBA, Vienna)
Sister chromatid cohesion is asymmetric
12:40 — 14:00
Lunch Break
15:10 — 15:45
15:45 — 19:00
JCP Reception & Museum Outing
March 12, 2024
10:30 — 11:05
11:05 — 11:40
Geoff Fudenberg (U of Southern California, Los Angeles)
Physical chemistry of interphase loop extrusion


Name Affiliation
Anton Goloborodko Institute of Molecular Biotechnology of the Austrian Academy of Sciences
Tamar Schlick New York University
Jan Smrek University of Vienna


Name Affiliation
Ivet Bahar Stony Brook University
Cleis Battaglia University of Edinburgh
David Brueckner Institute of Science and Technology Austria
Kerstin Bystricky University Toulouse Capitole
Buddhapriya Chakrabarti University of Sheffield
Tereza Clarence Icahn School of Medicine at Mount Sinai
Vlad Cojocaru Utrecht University and Babes-Bolyai University
Flavia Corsi Institute of Molecular Biotechnology of the Austrian Academy of Sciences
Maria Pia Cosma Center for Genomic Regulation
Dario Dasaro ENS de Lyon
Vladimir Dmitriev Institute of Molecular Biotechnology of the Austrian Academy of Sciences
Hatice Döşeme Izmir Biomedicine and Genome Center
Manuel Fernandez Merino Center for Genomic Regulation
Geoff Fudenberg University of Southern California
Sebastian Fürthauer Technical University of Vienna
Yuval Garini Technion Haifa
Oliver Gittus ENS de Lyon
Sergei Grigoryev The Pennsylvania State University
Alexander Grosberg New York University
Daniel Jost Ecole Normale Superieure de Lyon
Ariel Kaplan Technion Haifa
Mariana Kozlowska Karlsruhe Institute of Technology
Stephen Levene University of Texas, Dallas
Ludvig Lizana Umeå University
Alexandre Morozov Rutgers University
Lars Nordenskiöld Nanyang Technological University Singapore
Wilma Olson Rutgers University
Alexey Onufriev Virginia Polytechnic Institute and State University
Modesto Orozco Institute for Research in Biomedicine, Barcelona
Anna Panchenko Queen's University
Stephanie Portillo New York University
Angelo Rosa SISSA
Helmut Schiessel Technical University Dresden
Jakob Schindelwig Technical University of Vienna
Valerio Sorichetti Institute of Science and Technology Austria
Sarah Swygert Colorado State University
Mikhail Tamm Tallinn University
Vladimir Teif University of Essex
Matthew Thomas University of Edinburgh
Gasper Tkacik Institute of Science and Technology Austria
Luca Tubiana University of Trento
Serhan Turunç Izmir Biomedicine and Genome Center
Mattia Alberto Ubertini Friedrich Miescher Institute for Biomedical Research
John van Noort Leiden University
Peter Virnau Johannes-Gutenberg Universität Mainz
Preview of Alexey Onufriev - The nucleosome as the ``hydrogen atom" of epigenetics.
Alexey Onufriev (Virginia Tech): The nucleosome as the ``hydrogen atom" of epigenetics.
March 5, 2024 16:05 — 16:40
Preview of Daniel Jost - On the role of polymerases in shaping the 4D Genome
Daniel Jost (ENS Lyon): On the role of polymerases in shaping the 4D Genome
March 6, 2024 13:35 — 14:10
Preview of Anton Goloborodko - Sister chromatid cohesion is asymmetric
Anton Goloborodko (IMBA, Vienna): Sister chromatid cohesion is asymmetric
March 7, 2024 12:05 — 12:40
Preview of Alexandre Morozov - Statistical mechanics of chromatin structure and dynamics
Alexandre Morozov (Rutgers U): Statistical mechanics of chromatin structure and dynamics
March 12, 2024 10:30 — 11:05
At a glance
March 4, 2024 — March 15, 2024
ESI Boltzmann Lecture Hall
Anton Goloborodko (IMBA, Vienna)
Tamar Schlick (NYU, New York)
Jan Smrek (U of Vienna)