Restriction enzyme selection dictates detection range sensitivity in chromatin conformation capture-based variant-to-gene mapping approaches

Hum Genet. 2021 Oct;140(10):1441-1448. doi: 10.1007/s00439-021-02326-8. Epub 2021 Aug 18.

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.

Publication types

  • Comparative Study

MeSH terms

  • Chromatin / genetics*
  • Chromosome Mapping / methods*
  • DNA Restriction Enzymes / genetics*
  • Genetic Variation*
  • Genome-Wide Association Study / methods*
  • Humans
  • Promoter Regions, Genetic*

Substances

  • Chromatin
  • DNA Restriction Enzymes