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. Author manuscript; available in PMC: 2020 Dec 1.
Published in final edited form as: Trends Biochem Sci. 2019 Oct 31;44(12):1089–1090. doi: 10.1016/j.tibs.2019.09.006

Contact Mapping to Unravel Chromosome Folding

Tiffany Ge 1,2,4, Celeste D Rosencrance 1,2,4, Kyle P Eagen 1,2,3,*,@
PMCID: PMC7105279  NIHMSID: NIHMS1567380  PMID: 31677956

Summary Sections

Nuclear architecture has remained mysterious due to inadequate methods for observing DNA folding. New technologies aim to probe chromosome organization by mapping chromatin contacts. Chromosome conformation capture (3C) originally relied on chemical crosslinking of chromatin followed by proximity ligation to recover spatial information of neighboring genomic loci. Ligation-based methods have progressed from measuring pairwise contacts (Hi-C), to a handful (COLA, Tri-C, MC-4C) and dozens (C-walks) of interactions genome-wide.

Technologies based on proximity ligation inefficiently detect multiple interactions per locus. Ligation-free methods enhance the identification of higher-order interactions among distinct chromosomal regions as well as those within nuclear compartments. These novel methods provide unbiased spatial information from low cell inputs (Genome Architecture Mapping [GAM]), identify simultaneous interactions between multiple genomic loci (Split-pool Recognition of Interactions by Tag Extension [SPRITE]), and determine precise interactions at the single molecule level (ChIA-Drop).

Advantages

  • Hi-C
    • High-resolution (~1 kb) analysis possible
    • Reduced noise by enriching for ligation junctions
  • COLA
    • Shorter cross-linked fragments can recover more concatemers
  • C-Walks
    • Isolation of longer DNA concatamers can reveal hubs of interaction
  • COLA & C-walks
    • Can detect multiway interactions, beyond pairwise contacts
  • GAM
    • Captures multivalent interactions using only a small number of cells
    • Uniquely isolates nuclear slices versus processing of cross-linked chromatin
  • SPRITE
    • Maps both multiple DNA-DNA contacts as well as DNA-RNA contacts
    • Does not require encapsulation nor extensive whole genome amplification
  • ChIA-Drop
    • Single-molecule precision
    • Requires only a few thousand cells

Challenges

  • Hi-C, COLA, & C-Walks
    • Proximity ligation-based approach
    • Bulk, cell population data
  • Hi-C
    • Lower probability of capturing multiway interactions
  • COLA & C-Walks
    • Sparse data, particularly as the valency of interactions increases
  • GAM
    • Time-consuming
    • Requires special equipment and training
  • SPRITE
    • Relies on extensive fixation
  • ChIA-Drop
    • Background noise (singleton DNA fragments)
    • Comprehensiveness limited by number of droplet-containing chromatin complexes
    • Low resolution for mammalian systems

  • All methods infer, rather than directly observe, chromatin folding

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Acknowledgements

We are grateful to Haneen Ammouri and Qi Yu for helpful reading of this manuscript and apologize to those whose work could not be cited due to space limitations. Research in the Eagen Lab is supported by an NIH Director’s Early Independence Award DP5OD024587.

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