Cited by 189Genomics and Chromatin DynamicsChromatin Remodeling and CancerChromosomal and Genetic Variations

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Sequence-based modeling of three-dimensional genome architecture from kilobase to chromosome scale

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Zhou, Jian·2022·Nature Genetics

DOI 10.1038/s41588-022-01065-4PMC PMC9186125

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Abstract

To learn how genomic sequence influences multiscale three-dimensional (3D) genome architecture, this manuscript presents a sequence-based deep-learning approach, Orca, that predicts directly from sequence the 3D genome architecture from kilobase to whole-chromosome scale. Orca captures the sequence dependencies of structures including chromatin compartments and topologically associating domains, as well as diverse types of interactions from CTCF-mediated to enhancer-promoter interactions and Polycomb-mediated interactions with cell-type specificity. Orca enables various applications including predicting structural variant effects on multiscale genome organization and it recapitulated effects of experimentally studied variants at varying sizes (300 bp to 90 Mb). Moreover, Orca enables in silico virtual screens to probe the sequence basis of 3D genome organization at different scales. At the submegabase scale, it predicted specific transcription factor motifs underlying cell-type-specific genome interactions. At the compartment scale, virtual screens of sequence activities suggest a model for the sequence basis of chromatin compartments with a prominent role of transcription start sites.

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Authors: Zhou, J.
Affiliations: The University of Texas Southwestern Medical Center (US)
Corresponding author: Zhou, Jian
ORCID: Zhou, Jian
Venue: Nature Genetics
Publisher: Springer Science and Business Media LLC
Published: 2022-05
Volume: 54
Issue: 5
Pages: 725-734
ISSN: 1061-4036 (ISSN-L)
1546-1718
DOI: 10.1038/s41588-022-01065-4
PMC: PMC9186125
OpenAlex: W4280512834
Cited by: 177
References: 48
Citations by year: 2026: 45 · 2025: 36 · 2024: 49 · 2023: 31 · 2022: 15
FWCI: 11.00
Type: journal article
Language: en
Open access: green
doi.org
Licence: cc-by-nc-nd
www.springer.com/tdm (tdm)
www.springer.com/tdm (vor)
Locations: Nature Genetics (publishedVersion)
bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
PubMed (publishedVersion)
PubMed Central (acceptedVersion)
Funders: Cancer Prevention and Research Institute of Texas (RR190071)
U.S. Department of Health & Human Services | NIH | National Institute of General Medical Sciences (DP2GM146336)
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Chromatin Remodeling and Cancer
Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Chromosomal and Genetic Variations
Keywords: 3D genome organization, sequence-based prediction, ORCA, chromatin compartments, topologically associating domains, enhancer-promoter interactions, cell type specificity, transcription factor binding motifs, transcription start sites, virtual screening, deep learning
MeSH terms: Chromatin, Chromosomes, Promoter Regions, Genetic, Transcription Factors, Genome, Polycomb-Group Proteins

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Sequence-based modeling of three-dimensional genome architecture from kilobase to chromosome scale

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