Restriction enzyme selection dictates detection range sensitivity in chromatin conformation capture-based variant-to-gene mapping approaches
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Abstract
Promoter-focused chromatin conformation techniques directly detect interactions between gene promoters and distal genomic sequences, providing structural information relevant to gene regulation without the excessive non-genic architectural data generated by full-scale Hi-C. 3D promoter 'interactome' maps are crucial for understanding how epigenomic features such as histone modifications and open chromatin, or genetic variants identified in genome-wide association studies (GWAS), contribute to biological function. However, variation in sensitivity between such promoter-focused methods, principally due to restriction enzyme selection, has not been systematically assessed. Here, we performed a head-to-head comparison of promoter capture datasets using 4 cutters (DpnII or MboI) versus the 6 cutter HindIII from the same five cell types. While HindIII generally produces a higher signal-to-noise ratio for significant interactions in comparison to 4-cutters, we show that DpnII/MboI detects more proximal interactions and shows little overlap with the HindIII detection range. Promoter-interacting genomic regions mapped by 4-cutters are more enriched for regulatory features and disease-associated genetic variation than 6-cutters maps, suggesting that high-resolution maps better capture gene regulatory architectures than do lower resolution approaches.
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Our study improves on prior studies by utilizing the relatively frequent 4-cutter restriction enzyme DpnII, which generates smaller fragments with higher resolution across the entire genome.
“Our study improves on prior studies by utilizing a relatively frequent 4-cutter restriction enzyme, DpnII, which generates smaller fragments with higher resolution across the entire genome46.”
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Self-citation
- Authors
- Su, C., Pahl, M. C., Grant, S. F. A., & Wells, A. D.
- Affiliations
- Children's Hospital of Philadelphia (US)
- Corresponding author
- Grant, Struan F. A.
- Wells, Andrew D.
- Venue
- Human Genetics
- Published
- 2021-08-18
- Volume
- 140
- Issue
- 10
- Pages
- 1441-1448
- ISSN
- 0018-7348 (ISSN-L)
- 0340-6717
- 1432-1203
- PMC
- PMC9013487
- OpenAlex
- W3195184682
- Cited by
- 24
- References
- 7
- Citations by year
- 2026: 2 · 2025: 3 · 2024: 14 · 2023: 3 · 2022: 1 · 2021: 1
- FWCI
- 1.49
- Type
- journal article
- Language
- en
- Open access
- green
- doi.org
- Licence
- Locations
- Human Genetics (publishedVersion)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health (DK126194, 1R01AI137143, 5R01AG057516, R01DK122586, 2R01HD056465)
- 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 › Genetic Associations and Epidemiology
- Keywords
- restriction enzyme selection, chromosome conformation capture, MboI, HindIII, signal-to-noise ratio, gene expression regulation, disease-associated variants, epigenomic features, 3D genome organization
- MeSH terms
- Chromatin, Chromosome Mapping, DNA Restriction Enzymes, Humans, Promoter Regions, Genetic, Genetic Variation, Genome-Wide Association Study
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