Polymer physics predicts the effects of structural variants on chromatin architecture

Structural variants (SVs) can result in changes in gene expression due to abnormal chromatin folding and cause disease. However, the prediction of such effects remains a challenge. Here we present a polymer-physics-based approach (PRISMR) to model 3D chromatin folding and to predict enhancer–promoter contacts. PRISMR predicts higher-order chromatin structure from genome-wide chromosome conformation capture (Hi-C) data. Using the EPHA4 locus as a model, the effects of pathogenic SVs are predicted in silico and compared to Hi-C data generated from mouse limb buds and patient-derived fibroblasts. PRISMR deconvolves the folding complexity of the EPHA4 locus and identifies SV-induced ectopic contacts and alterations of 3D genome organization in homozygous or heterozygous states. We show that SVs can reconfigure topologically associating domains, thereby producing extensive rewiring of regulatory interactions and causing disease by gene misexpression. PRISMR can be used to predict interactions in silico, thereby providing a tool for analyzing the disease-causing potential of SVs.The authors present a polymer-physics-based approach (PRISMR) to model 3D chromatin folding and to predict enhancer–promoter contacts. PRISMR correctly predicts ectopic contacts induced by pathogenic SVs at the mouse Epha4 locus.

[1]  P. Gennes.  Scaling Concepts in Polymer Physics , 1979 .

[2]  C. D. Gelatt,et al.  Optimization by Simulated Annealing , 1983, Science.

[3]  Peter Salamon,et al.  Facts, Conjectures, and Improvements for Simulated Annealing , 1987 .

[4]  G. Parisi,et al.  Statistical Field Theory , 1988 .

[5]  G. Grest,et al.  Dynamics of entangled linear polymer melts: A molecular‐dynamics simulation , 1990 .

[6]  Steve Plimpton,et al.  Fast parallel algorithms for short-range molecular dynamics , 1993 .

[7]  Wouter de Laat,et al.  Quantitative analysis of chromosome conformation capture assays (3C-qPCR) , 2007, Nature Protocols.

[8]  Daniel Ruiz,et al.  A Fast Algorithm for Matrix Balancing , 2013, Web Information Retrieval and Linear Algebra Algorithms.

[9]  Dustin E. Schones,et al.  High-Resolution Profiling of Histone Methylations in the Human Genome , 2007, Cell.

[10]  Ralf Everaers,et al.  Structure and Dynamics of Interphase Chromosomes , 2008, PLoS Comput. Biol..

[11]  Mario Nicodemi,et al.  Thermodynamic pathways to genome spatial organization in the cell nucleus. , 2009, Biophysical journal.

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

[13]  William Stafford Noble,et al.  A Three-Dimensional Model of the Yeast Genome , 2010, Nature.

[14]  Dieter W. Heermann,et al.  Diffusion-Driven Looping Provides a Consistent Framework for Chromatin Organization , 2010, PloS one.

[15]  A. Hadjantonakis,et al.  Generation of chimeras by aggregation of embryonic stem cells with diploid or tetraploid mouse embryos. , 2011, Methods in molecular biology.

[16]  Mario Nicodemi,et al.  Conformation Regulation of the X Chromosome Inactivation Center: A Model , 2011, PLoS Comput. Biol..

[17]  William Stafford Noble,et al.  FIMO: scanning for occurrences of a given motif , 2011, Bioinform..

[18]  Mario Nicodemi,et al.  Complexity of chromatin folding is captured by the strings and binders switch model , 2012, Proceedings of the National Academy of Sciences.

[19]  Steven L Salzberg,et al.  Fast gapped-read alignment with Bowtie 2 , 2012, Nature Methods.

[20]  Data production leads,et al.  An integrated encyclopedia of DNA elements in the human genome , 2012 .

[21]  J. Sedat,et al.  Spatial partitioning of the regulatory landscape of the X-inactivation centre , 2012, Nature.

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

[23]  Jennifer E. Phillips-Cremins,et al.  Architectural Protein Subclasses Shape 3D Organization of Genomes during Lineage Commitment , 2013, Cell.

[24]  D. Marenduzzo,et al.  Nonspecific bridging-induced attraction drives clustering of DNA-binding proteins and genome organization , 2013, Proceedings of the National Academy of Sciences.

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

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

[27]  L. Vissers,et al.  Genome sequencing identifies major causes of severe intellectual disability , 2014, Nature.

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

[29]  Josée Dostie,et al.  An Overview of Genome Organization and How We Got There: from FISH to Hi-C , 2015, Microbiology and Molecular Reviews.

[30]  A. Visel,et al.  Disruptions of Topological Chromatin Domains Cause Pathogenic Rewiring of Gene-Enhancer Interactions , 2015, Cell.

[31]  M. K. Rudd,et al.  Next-generation sequencing of duplication CNVs reveals that most are tandem and some create fusion genes at breakpoints. , 2015, American journal of human genetics.

[32]  Neva C. Durand,et al.  Chromatin extrusion explains key features of loop and domain formation in wild-type and engineered genomes , 2015, Proceedings of the National Academy of Sciences.

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

[34]  Yannick G. Spill,et al.  Restraint‐based three‐dimensional modeling of genomes and genomic domains , 2015, FEBS letters.

[35]  S. Q. Xie,et al.  Hierarchical folding and reorganization of chromosomes are linked to transcriptional changes in cellular differentiation , 2015, Molecular systems biology.

[36]  L. Mirny,et al.  Formation of Chromosomal Domains in Interphase by Loop Extrusion , 2015, bioRxiv.

[37]  S. Mundlos,et al.  Formation of new chromatin domains determines pathogenicity of genomic duplications , 2016, Nature.

[38]  Neva C. Durand,et al.  Juicer Provides a One-Click System for Analyzing Loop-Resolution Hi-C Experiments. , 2016, Cell systems.

[39]  Simona Bianco,et al.  Polymer physics of chromosome large-scale 3D organisation , 2016, Scientific Reports.

[40]  Philip A. Ewels,et al.  HiCUP: pipeline for mapping and processing Hi-C data , 2015, F1000Research.

[41]  S. Mundlos,et al.  Breaking TADs: How Alterations of Chromatin Domains Result in Disease. , 2016, Trends in genetics : TIG.

[42]  Daniel S. Day,et al.  Activation of proto-oncogenes by disruption of chromosome neighborhoods , 2015, Science.

[43]  Alexander Schönhuth,et al.  A high-quality human reference panel reveals the complexity and distribution of genomic structural variants , 2016, Nature communications.

[44]  Martin Vingron,et al.  Characterization of hundreds of regulatory landscapes in developing limbs reveals two regimes of chromatin folding , 2017, Genome research.

[45]  L. Mirny,et al.  Targeted Degradation of CTCF Decouples Local Insulation of Chromosome Domains from Genomic Compartmentalization , 2017, Cell.