Free energy based high-resolution modeling of CTCF-mediated chromatin loops for human genome

A thermodynamic method for computing the stability and dynamics of chromatin loops is proposed. The CTCF-mediated interactions as observed in ChIA-PET experiments for human B-lymphoblastoid cells are evaluated in terms of a polymer model for chain folding physical properties and the experimentally observed frequency of contacts within the chromatin regions. To estimate the optimal free energy and a Boltzmann distribution of suboptimal structures, the approach uses dynamic programming with methods to handle degeneracy and heuristics to compute parallel and antiparallel chain stems and pseudoknots. Moreover, multiple loops mediated by CTCF proteins connected together and forming multimeric islands are simulated using the same model. Based on the thermodynamic properties of those topological three-dimensional structures, we predict the correlation between the relative activity of chromatin loop and the Boltzmann probability, or the minimum free energy, depending also on its genomic length. Segments of chromatin where the structures show a more stable minimum free energy (for a given genomic distance) tend to be inactive, whereas structures that have lower stability in the minimum free energy (with the same genomic distance) tend to be active.

[1]  Sigal Shachar,et al.  3D Chromosome Regulatory Landscape of Human Pluripotent Cells. , 2016, Cell stem cell.

[2]  W. Dawson,et al.  A physical origin for functional domain structure in nucleic acids as evidenced by cross-linking entropy: I. , 2001, Journal of theoretical biology.

[3]  W. Dawson,et al.  A new entropy model for RNA: part III. Is the folding free energy landscape of RNA funnel shaped? , 2014 .

[4]  Michele Di Pierro,et al.  A Transferable Model For Chromosome Architecture , 2016, bioRxiv.

[5]  A. West,et al.  Insulators: many functions, many mechanisms. , 2002, Genes & development.

[6]  P. Wolynes,et al.  Spin glasses and the statistical mechanics of protein folding. , 1987, Proceedings of the National Academy of Sciences of the United States of America.

[7]  Achilleas S Frangakis,et al.  Human mitotic chromosomes consist predominantly of irregularly folded nucleosome fibres without a 30‐nm chromatin structure , 2012, The EMBO journal.

[8]  Thomas G. Gilgenast,et al.  Local Genome Topology Can Exhibit an Incompletely Rewired 3D-Folding State during Somatic Cell Reprogramming. , 2016, Cell stem cell.

[9]  Andrea M. Chiariello,et al.  Polymer models of chromatin organization , 2013, Front. Genet..

[10]  Shihua He,et al.  Nuclear organization and chromatin dynamics--Sp1, Sp3 and histone deacetylases. , 2008, Advances in enzyme regulation.

[11]  Jinbo Xu,et al.  Inferential modeling of 3D chromatin structure , 2015, Nucleic acids research.

[12]  Yoshinori Nishino,et al.  Chromosomes without a 30-nm chromatin fiber , 2012, Nucleus.

[13]  Victor G Corces,et al.  Towards a predictive model of chromatin 3D organization. , 2016, Seminars in cell & developmental biology.

[14]  Ilya M. Flyamer,et al.  Active chromatin and transcription play a key role in chromosome partitioning into topologically associating domains , 2016, Genome research.

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

[16]  Simona Bianco,et al.  Polymer models of the organization of chromosomes in the nucleus of cells , 2015 .

[17]  Peter G Wolynes,et al.  Genomic Energy Landscapes. , 2017, Biophysical journal.

[18]  Dariusz M Plewczynski,et al.  CTCF-Mediated Human 3D Genome Architecture Reveals Chromatin Topology for Transcription , 2015, Cell.

[19]  T. Hirano,et al.  Chromosome Dynamics during Mitosis. , 2015, Cold Spring Harbor perspectives in biology.

[20]  Dariusz Plewczynski,et al.  3D-NOME: 3D NucleOme Multiscale Engine for data-driven modeling of three-dimensional genome architecture , 2016 .

[21]  Shihua He,et al.  Chromatin organization and nuclear microenvironments in cancer cells , 2008, Journal of cellular biochemistry.

[22]  Mario Nicodemi,et al.  A polymer model explains the complexity of large-scale chromatin folding , 2013, Nucleus.

[23]  A. Mirzabekov,et al.  Change in the pattern of histone binding to DNA upon transcriptional activation , 1989, Cell.

[24]  A. Murrell,et al.  Genomic Imprinting: CTCF Protects the Boundaries , 2004, Current Biology.

[25]  L. Mirny,et al.  The 3D Genome as Moderator of Chromosomal Communication , 2016, Cell.

[26]  R Eils,et al.  Compartmentalization of interphase chromosomes observed in simulation and experiment. , 1999, Journal of molecular biology.

[27]  J. Bujnicki,et al.  SimRNA: a coarse-grained method for RNA folding simulations and 3D structure prediction , 2015, Nucleic acids research.

[28]  W. Dawson,et al.  A new entropy model for RNA: part IV, The Minimum Free Energy (mFE) and the thermodynamically most-probable folding pathway (TMPFP) , 2015 .

[29]  Dario Meluzzi,et al.  Recovering ensembles of chromatin conformations from contact probabilities , 2012, Nucleic acids research.

[30]  Yann Ponty,et al.  VARNA: Interactive drawing and editing of the RNA secondary structure , 2009, Bioinform..

[31]  C. Crane-Robinson,et al.  The chromatin of active genes is not in a permanently open conformation. , 2009, Journal of molecular biology.

[32]  Howard Y. Chang,et al.  Single-cell chromatin accessibility reveals principles of regulatory variation , 2015, Nature.

[33]  M. L. Le Gros,et al.  Population-based 3D genome structure analysis reveals driving forces in spatial genome organization , 2016, Proceedings of the National Academy of Sciences.

[34]  Dariusz Plewczynski,et al.  An integrated 3-Dimensional Genome Modeling Engine for data-driven simulation of spatial genome organization , 2016, Genome research.

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

[36]  J. Davie,et al.  Nuclear matrix, dynamic histone acetylation and transcriptionally active chromatin , 1997, Molecular Biology Reports.

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

[38]  Wilma K Olson,et al.  Contributions of Sequence to the Higher-Order Structures of DNA. , 2017, Biophysical journal.

[39]  K Schulten,et al.  VMD: visual molecular dynamics. , 1996, Journal of molecular graphics.

[40]  J. Onuchic,et al.  Funnels, pathways, and the energy landscape of protein folding: A synthesis , 1994, Proteins.

[41]  E. Liu,et al.  An Oestrogen Receptor α-bound Human Chromatin Interactome , 2009, Nature.

[42]  W. Dawson,et al.  A new entropy model for RNA: part I. A critique of the standard Jacobson-Stockmayer model applied to multiple cross links , 2012 .

[43]  P. Hagerman.  Flexibility of DNA. , 1988, Annual review of biophysics and biophysical chemistry.

[44]  W. Dawson,et al.  Prediction of RNA Pseudoknots Using Heuristic Modeling with Mapping and Sequential Folding , 2007, PloS one.

[45]  Patrick Heun,et al.  Long-range compaction and flexibility of interphase chromatin in budding yeast analyzed by high-resolution imaging techniques. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[46]  Kazuhiro Maeshima,et al.  Chromatin structure: does the 30-nm fibre exist in vivo? , 2010, Current opinion in cell biology.

[47]  J. Onuchic,et al.  Theory of Protein Folding This Review Comes from a Themed Issue on Folding and Binding Edited Basic Concepts Perfect Funnel Landscapes and Common Features of Folding Mechanisms , 2022 .

[48]  Kentaro Shimizu,et al.  A new entropy model for RNA: part II. Persistence-related entropic contributions to RNA secondary structure free energy calculations , 2013 .

[49]  Tamar Schlick,et al.  Linking Chromatin Fibers to Gene Folding by Hierarchical Looping. , 2017, Biophysical journal.

[50]  Takaaki Hikima,et al.  Nucleosomal arrays self‐assemble into supramolecular globular structures lacking 30‐nm fibers , 2016, The EMBO journal.

[51]  Michael Q. Zhang,et al.  CRISPR Inversion of CTCF Sites Alters Genome Topology and Enhancer/Promoter Function , 2015, Cell.