Polymer physics predicts the effects of structural variants on chromatin architecture View Full Text


Ontology type: schema:ScholarlyArticle      Open Access: True


Article Info

DATE

2018-04-16

AUTHORS

Simona Bianco, Darío G. Lupiáñez, Andrea M. Chiariello, Carlo Annunziatella, Katerina Kraft, Robert Schöpflin, Lars Wittler, Guillaume Andrey, Martin Vingron, Ana Pombo, Stefan Mundlos, Mario Nicodemi

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. More... »

PAGES

662-667

Identifiers

URI

http://scigraph.springernature.com/pub.10.1038/s41588-018-0098-8

DOI

http://dx.doi.org/10.1038/s41588-018-0098-8

DIMENSIONS

https://app.dimensions.ai/details/publication/pub.1103265664

PUBMED

https://www.ncbi.nlm.nih.gov/pubmed/29662163


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33 schema:description 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.
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41 HI
42 PRISMR
43 abnormal chromatin folding
44 alterations
45 approach
46 architecture
47 buds
48 capture data
49 challenges
50 changes
51 chromatin architecture
52 chromatin folding
53 chromatin structure
54 chromosome conformation capture data
55 complexity
56 conformation capture (Hi-C) data
57 contact
58 data
59 disease
60 disease-causing potential
61 domain
62 ectopic contacts
63 effect
64 enhancer-promoter contacts
65 expression
66 extensive rewiring
67 fibroblasts
68 folding
69 gene expression
70 gene misexpression
71 genome organization
72 genome-wide chromosome conformation capture data
73 heterozygous state
74 higher-order chromatin structure
75 interaction
76 limb bud
77 loci
78 misexpression
79 model
80 mouse limb buds
81 organization
82 pathogenic structural variants
83 patient-derived fibroblasts
84 physics
85 polymer physics
86 potential
87 prediction
88 regulatory interactions
89 rewiring
90 silico
91 state
92 structural variants
93 structure
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