When TADs go bad: Chromatin structure and nuclear organisation in human disease
Open accessAbstract
Chromatin in the interphase nucleus is organised as a hierarchical series of structural domains, including self-interacting domains called topologically associating domains (TADs). This arrangement is thought to bring enhancers into closer physical proximity with their target genes, which often are located hundreds of kilobases away in linear genomic distance. TADs are demarcated by boundary regions bound by architectural proteins, such as CTCF and cohesin, although much remains to be discovered about the structure and function of these domains. Recent studies of TAD boundaries disrupted in engineered mouse models show that boundary mutations can recapitulate human developmental disorders as a result of aberrant promoter-enhancer interactions in the affected TADs. Similar boundary disruptions in certain cancers can result in oncogene overexpression, and CTCF binding sites at boundaries appear to be hyper-mutated across cancers. Further insights into chromatin organisation, in parallel with accumulating whole genome sequence data for disease cohorts, are likely to yield additional valuable insights into the roles of noncoding sequence variation in human disease.
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TADs appear to restrict the areas of enhancer action.
“Second, it was demonstrated that eukaryotic chromosomes are partitioned into so-called topologically associated domains (TADs) [35,36,37], which appear to restrict the areas of enhancer action [38,39,40,41].”
From Enhancer Function in the 3D Genome (2023) · cites this paper as [41]
The ability to establish contacts between enhancers and promoters is partially controlled at the level of chromosome organization into TADs, which in many cases limit the scope of enhancers.
“The ability to establish contacts between enhancers and promoters is partially controlled at the level of chromosome organization into topologically associated domains, which in many cases limit the scope of enhancers [38,41,130,131].”
From Enhancer Function in the 3D Genome (2023) · cites this paper as [41]
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Cited by
Sorted by citations
Enhancer Function in the 3D Genome
Razin, S. V., Ulianov, S. V., & Iarovaia, O. V. (2023) · Genes · doi:10.3390/genes14061277 · Cited by 15 · see citing works
- Authors
- Kaiser, V. B., & Semple, C. A.
- Affiliations
- Western General Hospital (GB)
- Corresponding author
- Kaiser, Vera B
- Venue
- F1000Research
- Publisher
- F1000 Research Ltd
- Published
- 2017-03-24
- Volume
- 6
- Pages
- 314
- ISSN
- 2046-1402 (ISSN-L)
- PMC
- PMC5373421
- OpenAlex
- W2597925416
- Cited by
- 64
- References
- 14
- Citations by year
- 2026: 1 · 2025: 4 · 2024: 4 · 2023: 5 · 2022: 6 · 2021: 8 · 2020: 10 · 2019: 10 · 2018: 13 · 2017: 3
- FWCI
- 0.92
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- F1000Research (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Edinburgh Research Explorer (University of Edinburgh) (submittedVersion, cc-by)
- Funders
- MRC core funding to the MRC Human Genetics Unit
- 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 › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Nuclear Structure and Function
- Keywords
- topologically associating domains, chromatin organization, TAD boundaries, CTCF, cohesin, enhancer-promoter interactions, developmental disorders, cancer, oncogene overexpression, chromatin structure
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