Bridging the Resolution Gap in Structural Modeling of 3D Genome Organization

Over the last decade, and especially after the advent of fluorescent in situ hybridization imaging and chromosome conformation capture methods, the availability of experimental data on genome three-dimensional organization has dramatically increased. We now have access to unprecedented details of how genomes organize within the interphase nucleus. Development of new computational approaches to leverage this data has already resulted in the first three-dimensional structures of genomic domains and genomes. Such approaches expand our knowledge of the chromatin folding principles, which has been classically studied using polymer physics and molecular simulations. Our outlook describes computational approaches for integrating experimental data with polymer physics, thereby bridging the resolution gap for structural determination of genomes and genomic domains.Spain. Ministerio de Ciencia e Innovación (BFU2010-19310)National Cancer Institute (U.S.)David H. Koch Institute for Integrative Cancer Research at MI

A Review of 2011 for PLoS Computational Biology

A Review of 2011 for <em>PLoS Computational Biology</em

Chromatin and epigenetics: current biophysical views

Recent advances in high-throughput sequencing experiments and their theoretical descriptions have determined fast dynamics of the "chromatin and epigenetics" field, with new concepts appearing at high rate. This field includes but is not limited to the study of DNA-protein-RNA interactions, chromatin packing properties at different scales, regulation of gene expression and protein trafficking in the cell nucleus, binding site search in the crowded chromatin environment and modulation of physical interactions by covalent chemical modifications of the binding partners. The current special issue does not pretend for the full coverage of the field, but it rather aims to capture its development and provide a snapshot of the most recent concepts and approaches. Eighteen open-access articles comprising this issue provide a delicate balance between current theoretical and experimental biophysical approaches to uncover chromatin structure and understand epigenetic regulation, allowing free flow of new ideas and preliminary results

Higher-order chromatin structure: bridging physics and biology

Advances in microscopy and genomic techniques have provided new insight into spatial chromatin organization inside of the nucleus. In particular, chromosome conformation capture data has highlighted the relevance of polymer physics for high-order chromatin organization. In this context, we review basic polymer states, discuss how an appropriate polymer model can be determined from experimental data, and examine the success and limitations of various polymer models of higher-order interphase chromatin organization. By taking into account topological constraints acting on the chromatin fiber, recently developed polymer models of interphase chromatin can reproduce the observed scaling of distances between genomic loci, chromosomal territories, and probabilities of contacts between loci measured by chromosome conformation capture methods. Polymer models provide a framework for the interpretation of experimental data as ensembles of conformations rather than collections of loops, and will be crucial for untangling functional implications of chromosomal organization.National Cancer Institute (U.S.). Physical Sciences-Oncology Center (MIT, (U54CA143874)

Hi-C-constrained physical models of human chromosomes recover functionally-related properties of genome organization

Combining genome-wide structural models with phenomenological data is at the forefront of efforts to understand the organizational principles regulating the human genome. Here, we use chromosome-chromosome contact data as knowledge-based constraints for large-scale three-dimensional models of the human diploid genome. The resulting models remain minimally entangled and acquire several functional features that are observed in vivo and that were never used as input for the model. We find, for instance, that gene-rich, active regions are drawn towards the nuclear center, while gene poor and lamina associated domains are pushed to the periphery. These and other properties persist upon adding local contact constraints, suggesting their compatibility with non-local constraints for the genome organization. The results show that suitable combinations of data analysis and physical modelling can expose the unexpectedly rich functionally-related properties implicit in chromosome-chromosome contact data. Specific directions are suggested for further developments based on combining experimental data analysis and genomic structural modelling

Graph rigidity reveals non-deformable collections of chromosome conformation constraints

Motivation: The physical structure of chromatin is associated with a variety of biological phenomena including long-range regulation, chromosome rearrangements, and somatic copy number alterations. Chromosome conformation capture is a recent experimental technique that results in pairwise proximity measurements between chromosome locations in a genome. This information can be used to construct three-dimensional models of portions of chromosomes or entire genomes using a variety of recently proposed algorithms. However, it is possible that these distance measurements do not provide the proper constraints to uniquely specify such an embedding. It is therefore necessary to separate regions of the chromatin structure that are sufficiently constrained from regions with measurements that suggest a more pliable structure. This separation will allow studies of correlations betweeen chromatin organization and genome function to be targeted to the sufficiently constrained, high-confidence substructures within an embedding. Results: Using rigidity theory, we introduce a novel, fast algorithm for identifying high-confidence (rigid) substructures within graphs that result from chromosome conformation capture experiments. We apply the method to four recent chromosome conformation capture data sets and find that for even stringently filtered experimental constraints, a large rigid region spans most of the genome. We find that the organization of rigid components depends crucially on short-range interactions within the genome. We also find that rigid component boundaries appear at regions associated with areas of low nucleosome density and that properties of rigid, subtelomeric regions are consistent with light microscopy data. Availability: The software for identifying rigid components is GPL-Licensed and available for download at http://www.cbcb.umd.edu/kingsford-group/starfish. Contact: [email protected] work was supported by the National Science Foundation [CCF-1053918, EF-0849899, and IIS-0812111 to C.K]; the National Institutes of Health [1R21AI085376 to C.K.]; and a Univeristy of Maryland Institute for Advanced Studies New Frontiers Award to C.K

The 4D Nucleome Project [preprint]

The spatial organization of the genome and its dynamics contribute to gene expression and cellular function in normal development as well as in disease. Although we are increasingly well equipped to determine a genome\u27s sequence and linear chromatin composition, studying the three-dimensional organization of the genome with high spatial and temporal resolution remains challenging. The 4D Nucleome Network aims to develop and apply approaches to map the structure and dynamics of the human and mouse genomes in space and time with the long term goal of gaining deeper mechanistic understanding of how the nucleus is organized. The project will develop and benchmark experimental and computational approaches for measuring genome conformation and nuclear organization, and investigate how these contribute to gene regulation and other genome functions. Further efforts will be directed at applying validated experimental approaches combined with biophysical modeling to generate integrated maps and quantitative models of spatial genome organization in different biological states, both in cell populations and in single cells

Exploring the three-dimensional organization of genomes: interpreting chromatin interaction data

How DNA is organized in three dimensions inside the cell nucleus and how this affects the ways in which cells access, read and interpret genetic information are among the longest standing questions in cell biology. Using newly developed molecular, genomic and computational approaches based on the chromosome conformation capture technology (such as 3C, 4C, 5C and Hi-C), the spatial organization of genomes is being explored at unprecedented resolution. Interpreting the increasingly large chromatin interaction data sets is now posing novel challenges. Here we describe several types of statistical and computational approaches that have recently been developed to analyse chromatin interaction data.National Institutes of Health (U.S.)National Human Genome Research Institute (U.S.) (HG003143)National Human Genome Research Institute (U.S.) (HG003143-06S1)W. M. Keck FoundationSpain. Ministerio de Ciencia e Innovación (BFU2010-19310/BMC)Human Frontier Science Program (Strasbourg, France) (RGP0044/2011)European Union (BLUEPRINT project (EU FP7 grant agreement 282510))National Cancer Institute (U.S.) (Physical Sciences Oncology Center at MIT, U54CA143874