Spatial patterns of CTCF sites define the anatomy of TADs and their boundaries
Open accessAbstract
Background: Topologically associating domains (TADs) are genomic regions of self-interaction. Additionally, it is known that TAD boundaries are enriched in CTCF binding sites. In turn, CTCF sites are known to be asymmetric, whereby the convergent configuration of a pair of CTCF sites leads to the formation of a chromatin loop in vivo. However, to date, it has been unclear how to reconcile TAD structure with CTCF-based chromatin loops. Results: We approach this problem by analysing CTCF binding site strengths and classifying clusters of CTCF sites along the genome on the basis of their relative orientation. Analysis of CTCF site orientation classes as a function of their spatial distribution along the human genome reveals that convergent CTCF site clusters are depleted while divergent CTCF clusters are enriched in the 5- to 100-kb range. We then analyse the distribution of CTCF binding sites as a function of TAD boundary conservation across seven primary human blood cell types. This reveals divergent CTCF site enrichment at TAD boundaries. Furthermore, convergent arrays of CTCF sites separate the left and right sections of TADs that harbour internal CTCF sites, resulting in unequal TAD ‘halves’. Conclusions: The orientation-based CTCF binding site cluster classification that we present reconciles TAD boundaries and CTCF site clusters in a mechanistically elegant fashion. This model suggests that the emergent structure of nuclear chromatin in the form of TADs relies on the obligate alternation of divergent and convergent CTCF site clusters that occur at different length scales along the genome. Graphical abstract:
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In the classic scenario, the boundary is presented by CTCF binding to its sequence motifs located in a divergent orientation at either end of the loop.
“In the classic scenario, this boundary is presented by CTCF binding to its sequence motifs located in a divergent orientation at either end of the loop [277, 438–440]”
From Transcriptional enhancers and their communication with gene promoters (2021) · cites this paper as [440]
The Results section reports that divergent CTCF-site patterns are enriched at TAD boundaries and suggests they confer boundary function (page not provided). But the paper distinguishes boundaries from loop ends: its Results section says loop bases involve pairs of convergent CTCF sites. It therefore does not support placing divergent motifs at either end of a loop. (LLM, conf=0.87)
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Transcriptional enhancers and their communication with gene promoters
Ray-Jones, H., & Spivakov, M. (2021) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-021-03903-w · Cited by 81 · see citing works
- Authors
- Nanni, L., Ceri, S., & Logie, C.
- Affiliations
- Politecnico di Milano (IT)
- Radboud University Nijmegen (NL)
- Corresponding author
- Logie, Colin
- Venue
- Genome Biology
- Published
- 2020-08-12
- Volume
- 21
- Issue
- 1
- Pages
- 197-197
- ISSN
- 1465-6906 (ISSN-L)
- 1474-760X
- PMC
- PMC7422557
- OpenAlex
- W3048801940
- Cited by
- 88
- References
- 23
- Citations by year
- 2026: 6 · 2025: 16 · 2024: 20 · 2023: 11 · 2022: 14 · 2021: 20 · 2020: 1
- FWCI
- 3.89
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Genome biology (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Virtual Community of Pathological Anatomy (University of Castilla La Mancha) (submittedVersion, cc-by)
- Radboud Repository (Radboud University) (submittedVersion, other-oa)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- H2020 European Research Council (693174)
- 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
- topologically associating domains, CTCF binding sites, TAD boundaries, chromatin looping, chromatin structure, 3D genome organization
- MeSH terms
- CCCTC-Binding Factor, Humans, Genome, Human
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