Polymer physics predicts the effects of structural variants on chromatin architecture

Item Type:	Article
Title:	Polymer physics predicts the effects of structural variants on chromatin architecture
Creators Name:	Bianco, S. and Lupiáñez, D.G. and Chiariello, A.M. and Annunziatella, C. and Kraft, K. and Schöpflin, R. and Wittler, L. and Andrey, G. and Vingron, M. and Pombo, A. and Mundlos, S. and Nicodemi, M.
Abstract:	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.
Keywords:	CCCTC-Binding Factor, Cell Line, Chromatin, Chromatin Assembly and Disassembly, Chromosomes, EphA4 Receptor, Gene Expression, Genetic Enhancer Elements, Genetic Promoter Regions, Inbred C57BL Mice, Polymers, Animals, Mice
Source:	Nature Genetics
ISSN:	1061-4036
Publisher:	Nature Publishing Group
Volume:	50
Number:	5
Page Range:	662-667
Date:	May 2018
Official Publication:	https://doi.org/10.1038/s41588-018-0098-8
PubMed:	View item in PubMed

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