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Topological domains in mammalian genomes identified by analysis of chromatin interactions
Open accessAbstract
The spatial organization of the genome is intimately linked to its biological function, yet our understanding of higher order genomic structure is coarse, fragmented and incomplete. In the nucleus of eukaryotic cells, interphase chromosomes occupy distinct chromosome territories, and numerous models have been proposed for how chromosomes fold within chromosome territories. These models, however, provide only few mechanistic details about the relationship between higher order chromatin structure and genome function. Recent advances in genomic technologies have led to rapid advances in the study of three-dimensional genome organization. In particular, Hi-C has been introduced as a method for identifying higher order chromatin interactions genome wide. Here we investigate the three-dimensional organization of the human and mouse genomes in embryonic stem cells and terminally differentiated cell types at unprecedented resolution. We identify large, megabase-sized local chromatin interaction domains, which we term 'topological domains', as a pervasive structural feature of the genome organization. These domains correlate with regions of the genome that constrain the spread of heterochromatin. The domains are stable across different cell types and highly conserved across species, indicating that topological domains are an inherent property of mammalian genomes. Finally, we find that the boundaries of topological domains are enriched for the insulator binding protein CTCF, housekeeping genes, transfer RNAs and short interspersed element (SINE) retrotransposons, indicating that these factors may have a role in establishing the topological domain structure of the genome.
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In the citing paper
“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 [36]
Experimental — accuracy not yet measuredThe cited source says what the claim attributes to it.
In the citing paper
“metazoan genomes are organised into megabase-scale segregated domains that are often invariant between cell types, termed topologically associating domains (TADs) [432–434].”
From Transcriptional enhancers and their communication with gene promoters (2021) · cites this paper as [432]
In the citing paper
“loop extrusion mediated by cohesin and CTCF mediates the formation of chromatin loops and self-interacting Topologically Associating Domains (TADs)”
From Neuronal DNA double-strand breaks lead to genome structural variations and 3D genome disruption in neurodegeneration (2023) · cites this paper as [84]
In the citing paper
“The mouse α-globin cluster is located in close proximity to a cluster of 10 widely expressed genes near the boundary of a ~1Mb TAD as defined by Dixon et al (Fig. 1A)12.”
From Tissue-specific CTCF-cohesin-mediated chromatin architecture delimits enhancer interactions and function in vivo (2017) · cites this paper as [12]
In the citing paper
“Mammalian genomes are organized into a hierarchy of Megabase (Mb)-scale topologically associating domains (TADs) (Dixon et al., 2012; Nora et al., 2012) and smaller, nested subTADs (Dixon et al., 2012; Nora et al., 2012; Phillips-Cremins et al., 2013; Rao et al., 2014).”
From Disease-Associated Short Tandem Repeats Co-localize with Chromatin Domain Boundaries (2018) · cites this paper as Dixon et al., 2012
In the citing paper
“Consistent with previous reports, we found enrichment for the architectural protein CCCTC-binding factor (CTCF) at human ES cell boundaries compared to loci internal to domains (Figure S6A-B) (Dixon et al., 2012; Nora et al., 2012; Phillips-Cremins et al., 2013).”
From Disease-Associated Short Tandem Repeats Co-localize with Chromatin Domain Boundaries (2018) · cites this paper as Dixon et al., 2012
In the citing paper
“At intermediate scales (100 kb to 1 Mb), a major discovery is the existence of topologically associating domains (TADs) (Dixon et al., 2012, Nora et al., 2012, Sexton et al., 2012).”
From Multiscale 3D Genome Rewiring during Mouse Neural Development (2017) · cites this paper as Dixon et al., 2012
In the citing paper
“The third set of boundaries appear to represent repeats (Figure 2B), consistent with previous findings (Dixon et al., 2012).”
From Multiscale 3D Genome Rewiring during Mouse Neural Development (2017) · cites this paper as Dixon et al., 2012
In the citing paper
“Therefore, although we confirmed that most TAD boundaries are conserved (Dixon et al., 2012), novel borders can occur at promoters of developmentally regulated genes.”
From Multiscale 3D Genome Rewiring during Mouse Neural Development (2017) · cites this paper as Dixon et al., 2012
In the citing paper
“Recent chromosome conformation studies have revealed that mammalian chromosomes are structured into largely tissue-invariant TADs in which the DNA interactions are more frequent within a given domain than with regions in other domains4,5.”
From Disruption of chromatin folding domains by somatic genomic rearrangements in human cancer (2020) · cites this paper as [4]
In the citing paper
“Furthermore, we observed known TAD boundary signatures4 around our boundary calls for each cell type (Extended Data Fig. 1c).”
From Disruption of chromatin folding domains by somatic genomic rearrangements in human cancer (2020) · cites this paper as [4]
In the citing paper
“The median distance between the common boundaries was approximately 750 kb, consistent with the reported median TAD size in human cells4,19 (Extended Data Fig. 1e).”
From Disruption of chromatin folding domains by somatic genomic rearrangements in human cancer (2020) · cites this paper as [4]
In the citing paper
“Furthermore, it has also been suggested that SVs could lead to TAD fusions40 (also referred to as neo-TADs3,4);”
From Disruption of chromatin folding domains by somatic genomic rearrangements in human cancer (2020) · cites this paper as [4]
In the citing paper
“TADs were identified through Hi-C3,4 and their existence have since been confirmed by alternative methods such as intrinsic 3C (i3C),18 which avoids the cross-linking step and Genome Architecture Mapping (GAM),19 which avoids the ligation step.”
From Recent evidence that TADs and chromatin loops are dynamic structures (2018) · cites this paper as [4]
In the citing paper
“TADs are somewhat conserved between different cell types and different species.4,20”
From Recent evidence that TADs and chromatin loops are dynamic structures (2018) · cites this paper as [4]
In the citing paper
“First, chromatin is organized into Topological Associating Domains (TADs) that are characterized by preferential contacts between loci inside the same TAD and insulation from loci in adjacent TADs.3,4”
From Recent evidence that TADs and chromatin loops are dynamic structures (2018) · cites this paper as [4]
In the citing paper
“suggesting an important functional role of CTCF and cohesin in TAD formation and maintenance (Fig. 2A).”
From Recent evidence that TADs and chromatin loops are dynamic structures (2018) · cites this paper as [4]
In the citing paper
“Finally, ∼18% of TAD boundaries appear to be partially resistant to CTCF loss,10 suggesting that additional boundary factors, such as active promoters4 since engaged RNA Pol II can block cohesin extrusion46 as well as alternative architectural factors, may also play a role.”
From Recent evidence that TADs and chromatin loops are dynamic structures (2018) · cites this paper as [4]
In the citing paper
“After TADs were discovered through Hi-C studies, it quickly became clear that TAD boundaries are near universally enriched in CTCF and cohesin ChIP-Seq peaks,3,4,16”
From Recent evidence that TADs and chromatin loops are dynamic structures (2018) · cites this paper as [4]
In the citing paper
“These TADs, which have similar boundaries in all human cell types examined, have been proposed to constrain enhancer-gene interactions because most DNA contacts occur within the TADs (Dixon et al., 2015; Dixon et al., 2012).”
From Insulated Neighborhoods: Structural and Functional Units of Mammalian Gene Control (2016) · cites this paper as Dixon et al., 2012
In the citing paper
“These TADs, which have similar boundaries in all human cell types examined, have been proposed to constrain enhancer-gene interactions because most DNA contacts occur within the TADs (Dixon et al., 2015; Dixon et al., 2012).”
From Insulated Neighborhoods: Structural and Functional Units of Mammalian Gene Control (2016) · cites this paper as Dixon et al., 2012
In the citing paper
“Furthermore, individual chromosomes are partitioned into megabase- sized topologically associating domains (TADs), regions with relatively high intradomain DNA interaction frequencies as measured by Hi-C chromosome conformation capture data (Dixon et al., 2012; Nora et al., 2012).”
From Insulated Neighborhoods: Structural and Functional Units of Mammalian Gene Control (2016) · cites this paper as Dixon et al., 2012
In the citing paper
“Nonetheless, the TADs identified by processing Hi-C data with the Hidden Markov algorithm (Dixon et al., 2012; Nora et al., 2012) can also be identified when this algorithm is used to process cohesin ChIA-PET data (Ji et al., 2016).”
From Insulated Neighborhoods: Structural and Functional Units of Mammalian Gene Control (2016) · cites this paper as Dixon et al., 2012
In the citing paper
“Studies on TADs have estimated that most TAD boundaries are shared by any two cell types (Dixon et al., 2015; Dixon et al., 2012).”
From Insulated Neighborhoods: Structural and Functional Units of Mammalian Gene Control (2016) · cites this paper as Dixon et al., 2012
In the citing paper
“the striking similarity of TAD boundaries across cell types (Dixon et al., 2015; Dixon et al., 2012)”
From Insulated Neighborhoods: Structural and Functional Units of Mammalian Gene Control (2016) · cites this paper as Dixon et al., 2012
In the citing paper
“genome-wide, high-resolution understanding of chromosome cell-cycle dynamics11 is still limited by current technologies”
From Cell-cycle dynamics of chromosomal organization at single-cell resolution (2017) · cites this paper as [5]
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Metadata
- Authors
- Dixon, J. R., Selvaraj, S., Yue, F., Kim, A., Li, Y., Shen, Y., Hu, M., Liu, J. S., & Ren, B.
- Affiliations
- Ludwig Cancer Research (BE)
- Harvard University (US)
- Corresponding author
- Ren, Bing
- Venue
- Nature
- Published
- 2012-04-11
- Volume
- 485
- Issue
- 7398
- Pages
- 376-380
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC3356448
- OpenAlex
- W2070021921
- Cited by
- 6,829
- References
- 33
- Citations by year
- 2026: 356 · 2025: 432 · 2024: 550 · 2023: 544 · 2022: 567 · 2021: 690 · 2020: 661 · 2019: 629 · 2018: 568 · 2017: 524 · 2016: 423 · 2015: 351 · 2014: 237 · 2013: 220 · 2012: 66
- FWCI
- 112.45
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Digital Access to Scholarship at Harvard (DASH) (Harvard University) (submittedVersion, cc-by)
- RePEc: Research Papers in Economics (submittedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- Centers for Disease Control and Prevention (R01GH003991)
- National Human Genome Research Institute (R01HG003991)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Chromosomal and Genetic Variations
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Chromatin Remodeling and Cancer
- Keywords
- topological domains, 3D genome organization, chromatin interactions, topologically associating domains, Hi-C, 5C, mouse X chromosome, X inactivation center, CTCF, heterochromatin, chromosome territories, embryonic stem cells, SINE retrotransposons
- MeSH terms
- CCCTC-Binding Factor, Animals, Binding Sites, Cell Differentiation, Chromatin, Chromosomes, Female, Heterochromatin, Humans, Male, Mammals, Repressor Proteins, RNA, Transfer, Genome, Evolution, Molecular, Genes, Essential, Short Interspersed Nucleotide Elements, Mice, Embryonic Stem Cells
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