Assessing the limits of restraint-based 3D modeling of genomes and genomic domains

Restraint-based modeling of genomes has been recently explored with the advent of Chromosome Conformation Capture (3C-based) experiments. We previously developed a reconstruction method to resolve the 3D architecture of both prokaryotic and eukaryotic genomes using 3C-based data. These models were congruent with fluorescent imaging validation. However, the limits of such methods have not systematically been assessed. Here we propose the first evaluation of a mean-field restraint-based reconstruction of genomes by considering diverse chromosome architectures and different levels of data noise and structural variability. The results show that: first, current scoring functions for 3D reconstruction correlate with the accuracy of the models; second, reconstructed models are robust to noise but sensitive to structural variability; third, the local structure organization of genomes, such as Topologically Associating Domains, results in more accurate models; fourth, to a certain extent, the models capture the intrinsic structural variability in the input matrices and fifth, the accuracy of the models can be a priori predicted by analyzing the properties of the interaction matrices. In summary, our work provides a systematic analysis of the limitations of a mean-field restrain-based method, which could be taken into consideration in further development of methods as well as their applications.

[1]  Ian H. Witten,et al.  The WEKA data mining software: an update , 2009, SKDD.

[2]  Edith Heard,et al.  Segmental folding of chromosomes: A basis for structural and regulatory chromosomal neighborhoods? , 2013, BioEssays : news and reviews in molecular, cellular and developmental biology.

[3]  Neva C. Durand,et al.  A 3D Map of the Human Genome at Kilobase Resolution Reveals Principles of Chromatin Looping , 2014, Cell.

[4]  Zhaohui S. Qin,et al.  Gene density, transcription, and insulators contribute to the partition of the Drosophila genome into physical domains. , 2012, Molecular cell.

[5]  Eric S. Lander,et al.  A 3D Map of the Human Genome at Kilobase Resolution Reveals Principles of Chromatin Looping , 2015, Cell.

[6]  Ben M. Webb,et al.  Putting the Pieces Together: Integrative Modeling Platform Software for Structure Determination of Macromolecular Assemblies , 2012, PLoS biology.

[7]  T. Misteli.  Beyond the Sequence: Cellular Organization of Genome Function , 2011 .

[8]  Ivan Junier,et al.  Spatial and Topological Organization of DNA Chains Induced by Gene Co-localization , 2010, PLoS Comput. Biol..

[9]  J. Dekker,et al.  Predictive Polymer Modeling Reveals Coupled Fluctuations in Chromosome Conformation and Transcription , 2014, Cell.

[10]  Marc A. Martí-Renom,et al.  The Three-Dimensional Architecture of a Bacterial Genome and Its Alteration by Genetic Perturbation , 2012, RECOMB.

[11]  Ming Hu,et al.  Bayesian Inference of Spatial Organizations of Chromosomes , 2013, PLoS Comput. Biol..

[12]  J. Dekker,et al.  Hi-C: a comprehensive technique to capture the conformation of genomes. , 2012, Methods.

[13]  Peter Fraser,et al.  Gene regulation through nuclear organization , 2007, Nature Structural &Molecular Biology.

[14]  Marc A. Martí-Renom,et al.  Bridging the Resolution Gap in Structural Modeling of 3D Genome Organization , 2011, PLoS Comput. Biol..

[15]  Marc A Marti-Renom,et al.  The Three-dimensional Architecture of a Bacterial Genome and Its Alteration by Genetic Perturbation , 2022 .

[16]  E. C. Schirmer,et al.  Nuclear envelope: connecting structural genome organization to regulation of gene expression. , 2014, Advances in experimental medicine and biology.

[17]  Marc A Marti-Renom,et al.  Genome structure determination via 3C-based data integration by the Integrative Modeling Platform. , 2012, Methods.

[18]  L. Mirny,et al.  Exploring the three-dimensional organization of genomes: interpreting chromatin interaction data , 2013, Nature Reviews Genetics.

[19]  A. Tanay,et al.  Single cell Hi-C reveals cell-to-cell variability in chromosome structure , 2013, Nature.

[20]  L. Mirny,et al.  Biological techniques: Chromosomes captured one by one , 2013, Nature.

[21]  Kurt Binder,et al.  Monte Carlo Simulations in Statistical Physics , 2009, Encyclopedia of Complexity and Systems Science.

[22]  J. Dekker,et al.  Capturing Chromosome Conformation , 2002, Science.

[23]  J. Lawrence,et al.  The three-dimensional folding of the α-globin gene domain reveals formation of chromatin globules , 2011, Nature Structural &Molecular Biology.

[24]  Reza Kalhor,et al.  Genome architectures revealed by tethered chromosome conformation capture and population-based modeling , 2011, Nature Biotechnology.

[25]  Guillaume J. Filion,et al.  Distinct structural transitions of chromatin topological domains correlate with coordinated hormone-induced gene regulation , 2014, Genes & development.

[26]  Ivan Junier,et al.  Polymer modeling of the E. coli genome reveals the involvement of locus positioning and macrodomain structuring for the control of chromosome conformation and segregation , 2013, Nucleic acids research.

[27]  Jesse R. Dixon,et al.  Topological Domains in Mammalian Genomes Identified by Analysis of Chromatin Interactions , 2012, Nature.

[28]  A. Lesne,et al.  3D genome reconstruction from chromosomal contacts , 2014, Nature Methods.

[29]  L. Mirny,et al.  Iterative Correction of Hi-C Data Reveals Hallmarks of Chromosome Organization , 2012, Nature Methods.

[30]  V. Corces,et al.  CTCF: an architectural protein bridging genome topology and function , 2014, Nature Reviews Genetics.

[31]  L. Mirny,et al.  High-Resolution Mapping of the Spatial Organization of a Bacterial Chromosome , 2013, Science.

[32]  William Stafford Noble,et al.  A statistical approach for inferring the 3D structure of the genome , 2014, Bioinform..

[33]  Daniel Capurso,et al.  Reproducibility of 3D chromatin configuration reconstructions. , 2014, Biostatistics.

[34]  I. Amit,et al.  Comprehensive mapping of long range interactions reveals folding principles of the human genome , 2011 .

[35]  T. Cremer,et al.  Chromosome territories, nuclear architecture and gene regulation in mammalian cells , 2001, Nature Reviews Genetics.

[36]  David L. Copolov,et al.  Human Frontiers Science Program , 1994 .

[37]  Ryan K. Dale,et al.  CTCF-mediated transcriptional regulation through cell type-specific chromosome organization in the β-globin locus , 2012, Nucleic acids research.