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Enhancer hubs and loop collisions identified from single-allele topologies
Amin Allahyar1,2, Carlo Vermeulen3, Britta A M Bouwman3
1Center for Molecular Medicine, University Medical Center, Utrecht University, Utrecht, the Netherlands.
Nature Genetics
|July 11, 2018
Summary
Multi-contact 4C (MC-4C) uses Nanopore sequencing to reveal simultaneous DNA interactions on single alleles. This method uncovers novel chromatin structures and enhancer-gene interactions, advancing our understanding of genome folding.
Area of Science:
- Genomics
- Molecular Biology
- Epigenetics
Background:
- Chromatin folding regulates gene activity and genome topology.
- Current methods analyze pairwise contacts in cell populations, limiting insight into simultaneous or competitive interactions.
- Distinguishing simultaneous from competitive DNA interactions is crucial for understanding gene regulation.
Purpose of the Study:
- To introduce multi-contact 4C (MC-4C) for analyzing multi-way DNA conformations on individual alleles.
- To differentiate cooperative, random, and competing chromatin interactions.
- To identify novel genomic structures and regulatory mechanisms in subpopulations of cells.
Main Methods:
- Application of Nanopore sequencing to 4C (4C-seq) for multi-contact analysis.
- Development of MC-4C to study single-allele DNA conformations.
- Analysis of chromatin interactions in specific genomic regions, including the β-globin superenhancer.
Main Results:
- MC-4C successfully distinguishes simultaneous from competing DNA interactions at single-allele resolution.
- Identified an enhancer hub within the β-globin superenhancer accommodating two genes simultaneously.
- Observed rosette-like structures formed by colliding CTCF-bound anchors, particularly in WAPL-deficient cells, indicative of 'cohesin traffic jams'.
Conclusions:
- Single-allele topology studies provide unprecedented resolution for understanding genome folding mechanisms.
- MC-4C is a powerful tool for dissecting complex chromatin interactions and their functional consequences.
- The findings offer new insights into enhancer function and the role of cohesin dynamics in genome organization.
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