Enhancer hubs and loop collisions identified from single-allele topologies
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Abstract
Chromatin folding contributes to the regulation of genomic processes such as gene activity. Existing conformation capture methods characterize genome topology through analysis of pairwise chromatin contacts in populations of cells but cannot discern whether individual interactions occur simultaneously or competitively. Here we present multi-contact 4C (MC-4C), which applies Nanopore sequencing to study multi-way DNA conformations of individual alleles. MC-4C distinguishes cooperative from random and competing interactions and identifies previously missed structures in subpopulations of cells. We show that individual elements of the β-globin superenhancer can aggregate into an enhancer hub that can simultaneously accommodate two genes. Neighboring chromatin domain loops can form rosette-like structures through collision of their CTCF-bound anchors, as seen most prominently in cells lacking the cohesin-unloading factor WAPL. Here, massive collision of CTCF-anchored chromatin loops is believed to reflect 'cohesin traffic jams'. Single-allele topology studies thus help us understand the mechanisms underlying genome folding and functioning.
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The LCR in the β-globin locus can simultaneously engage two adult globin genes, Hbb-b1 and Hbb-b2, while skipping over embryonic globin genes, in mouse fetal liver cells.
“the LCR in the β-globin locus can simultaneously engage two adult globin genes, Hbb-b1 and Hbb-b2, while skipping over embryonic globin genes, in mouse fetal liver cells [485].”
From Transcriptional enhancers and their communication with gene promoters (2021) · cites this paper as [485]
Tri-C and MC-4C provided evidence for higher-order hubs containing three and more regulatory elements in the α- and β-globin loci.
“Both technologies, applied in the α- and β- globin loci respectively, provided evidence for higher-order hubs, containing three and more regulatory elements [499, 485].”
From Transcriptional enhancers and their communication with gene promoters (2021) · cites this paper as [485]
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- Authors
- Allahyar, A., Vermeulen, C., Bouwman, B. A. M., Krijger, P. H. L., Verstegen, M. J. A. M., Geeven, G., van Kranenburg, M., Pieterse, M., Straver, R., Haarhuis, J. H. I., Jalink, K., Teunissen, H., Renkens, I. J., Kloosterman, W. P., Rowland, B. D., de Wit, E., de Ridder, J., & de Laat, W.
- Affiliations
- Utrecht University (NL)
- University Medical Center Utrecht (NL)
- The Netherlands Cancer Institute (NL)
- ORCID
- Venue
- Nature Genetics
- Published
- 2018-07-09
- Volume
- 50
- Issue
- 8
- Pages
- 1151-1160
- ISSN
- 1061-4036 (ISSN-L)
- 1546-1718
- OpenAlex
- W2812344549
- Cited by
- 227
- References
- 14
- Citations by year
- 2026: 7 · 2025: 18 · 2024: 22 · 2023: 24 · 2022: 33 · 2021: 35 · 2020: 40 · 2019: 35 · 2018: 13
- FWCI
- 10.94
- Type
- journal article
- Language
- en
- Open access
- green
- doi.org
- Licence
- cc-by-nc-nd
- www.springer.com/tdm (tdm)
- Locations
- Nature Genetics (publishedVersion)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- Utrecht University Repository (Utrecht University) (submittedVersion, other-oa)
- KNAW research portal (Royal Academy of Art and Sciences (KNAW)) (submittedVersion)
- KNAW Research Portal (The Royal Netherlands Academy of Arts and Sciences) (submittedVersion)
- Utrecht University Repository (Utrecht University) (submittedVersion)
- Funders
- Nederlandse Organisatie voor Wetenschappelijk Onderzoek (016.161.316, 639.072.715)
- National Institutes of Health
- National Cancer Institute (U01CA200147)
- 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 › Agricultural and Biological Sciences › Plant Science › Chromosomal and Genetic Variations
- Keywords
- chromatin folding, WAPL, nanopore sequencing
- MeSH terms
- CCCTC-Binding Factor, Alleles, Animals, Chromatin, Enhancer Elements, Genetic, Nucleic Acid Conformation, Regulatory Sequences, Nucleic Acid, Mice, beta-Globins
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