The DOI matches its Crossref record; 31 of the 32 references it cites were found in a registry or an index.
Spatial partitioning of the regulatory landscape of the X-inactivation centre
Open accessAbstract
In eukaryotes transcriptional regulation often involves multiple long-range elements and is influenced by the genomic environment. A prime example of this concerns the mouse X-inactivation centre (Xic), which orchestrates the initiation of X-chromosome inactivation (XCI) by controlling the expression of the non-protein-coding Xist transcript. The extent of Xic sequences required for the proper regulation of Xist remains unknown. Here we use chromosome conformation capture carbon-copy (5C) and super-resolution microscopy to analyse the spatial organization of a 4.5-megabases (Mb) region including Xist. We discover a series of discrete 200-kilobase to 1 Mb topologically associating domains (TADs), present both before and after cell differentiation and on the active and inactive X. TADs align with, but do not rely on, several domain-wide features of the epigenome, such as H3K27me3 or H3K9me2 blocks and lamina-associated domains. TADs also align with coordinately regulated gene clusters. Disruption of a TAD boundary causes ectopic chromosomal contacts and long-range transcriptional misregulation. The Xist/Tsix sense/antisense unit illustrates how TADs enable the spatial segregation of oppositely regulated chromosomal neighbourhoods, with the respective promoters of Xist and Tsix lying in adjacent TADs, each containing their known positive regulators. We identify a novel distal regulatory region of Tsix within its TAD, which produces a long intervening RNA, Linx. In addition to uncovering a new principle of cis-regulatory architecture of mammalian chromosomes, our study sets the stage for the full genetic dissection of the X-inactivation centre.
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“Consistent with prior studies16, we found that genes in the same domain correlate across samples, but that genes separated by a boundary show lower correlation (Fig. 1e).”
From Insulator dysfunction and oncogene activation in IDH mutant gliomas (2016) · cites this paper as [16]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“Consistent with prior studies16, we found that genes in the same domain correlate across samples, but that genes separated by a boundary show lower correlation (Fig. 1e).”
From Insulator dysfunction and oncogene activation in IDH mutant gliomas (2016) · cites this paper as [16]
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 [433]
The cited source says what the claim attributes to it.
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 [35]
In the citing paper
“Indeed, the genome is now known to be hierarchically organized in a series of 3D structures, starting from nucleosome clutches, to chromatin loops, to chromosomal domains called topologically associating domains (TADs), and finally to active or repressive compartments and chromosome territories 15,46,[48][49][50] .”
From Advances in epigenetics link genetics to the environment and disease (2019) · cites this paper as [48]
In the citing paper
“These changes enable proceeding through the 3C protocol in a single tube per sample, allow handling of over 20 samples in parallel, reduce the amount of cells needed by a factor 5 to 10 and cut down the time needed to complete the protocol from 8 days (Nora et al. 2012) to 4 days.”
From Targeted Degradation of CTCF Decouples Local Insulation of Chromosome Domains from Genomic Compartmentalization (2017) · cites this paper as Nora et al. 2012
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 [85]
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 Nora 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 Nora et al., 2012
In the citing paper
“The deposition of chromatin marks is thought to contribute to this process (Dixon et al., 2015, Nora et al., 2012)”
From Multiscale 3D Genome Rewiring during Mouse Neural Development (2017) · cites this paper as Nora 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 Nora 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 [5]
In the citing paper
“The disruption of domain boundaries can result in ectopic interactions between neighboring domains and affect the regulation of nearby genes5,9.”
From Disruption of chromatin folding domains by somatic genomic rearrangements in human cancer (2020) · cites this paper as [5]
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 [3]
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 [3]
In the citing paper
“A large body of evidence suggests that TADs correspond to functional regulatory domains by primarily restricting contact between enhancers and promoters to occur within the same TAD3,21–25”
From Recent evidence that TADs and chromatin loops are dynamic structures (2018) · cites this paper as [3]
In the citing paper
“Accordingly, deletion of a boundary between two TADs causes ectopic contacts between previously insulated loci3 and can cause aberrant gene expression through improper enhancer-promoter contact.27,28”
From Recent evidence that TADs and chromatin loops are dynamic structures (2018) · cites this paper as [3]
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 [3]
In the citing paper
“Both DNA FISH3,9,36–39 and single-cell Hi-C40,41 studies show that genome organization is highly variable between cells and that even strong Hi-C loop anchors only contact in a small subset of cells”
From Recent evidence that TADs and chromatin loops are dynamic structures (2018) · cites this paper as [3]
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 [3]
In the citing paper
“The CTCF/cohesin anchored loop domain matching the Hi-C corner-peak actually only exists in a small subset of cells, which is also consistent with the high levels of cell-to-cell variability in contact probability observed in DNA FISH studies.3,9,36–39”
From Recent evidence that TADs and chromatin loops are dynamic structures (2018) · cites this paper as [3]
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 Nora 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 Nora 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 [4]
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Metadata
- Authors
- Nora, E. P., Lajoie, B. R., Schulz, E. G., Giorgetti, L., Okamoto, I., Servant, N., Piolot, T., van Berkum, N. L., Meisig, J., Sedat, J., Gribnau, J., Barillot, E., Blüthgen, N., Dekker, J., & Heard, E.
- Affiliations
- Institut Curie (FR)
- University of Massachusetts Chan Medical School (US)
- Centre National de la Recherche Scientifique (FR)
- Inserm (FR)
- Humboldt-Universität zu Berlin (DE)
- University of California, San Francisco (US)
- Erasmus MC (NL)
- Corresponding author
- Dekker, Job
- ORCID
- Venue
- Nature
- Published
- 2012-04-11
- Volume
- 485
- Issue
- 7398
- Pages
- 381-385
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC3555144
- OpenAlex
- W2161212572
- Cited by
- 2,895
- References
- 32
- Citations by year
- 2026: 145 · 2025: 168 · 2024: 181 · 2023: 213 · 2022: 241 · 2021: 276 · 2020: 255 · 2019: 300 · 2018: 247 · 2017: 241 · 2016: 201 · 2015: 173 · 2014: 112 · 2013: 103 · 2012: 34
- FWCI
- 50.79
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- EUR Research Repository (Erasmus University Rotterdam) (publishedVersion)
- PubMed Central (acceptedVersion)
- MPG.PuRe (Max Planck Society) (submittedVersion, other-oa)
- The Journal of the American Medical Association (JAMA) Network (American Medical Association) (submittedVersion)
- EUR Research Repository (Erasmus University Rotterdam) (submittedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Max Planck Digital Library (submittedVersion, other-oa)
- Funders
- W. M. Keck Foundation
- European Commission (257082, 242129)
- Agence Nationale de la Recherche (ANR-10-INBS-0009)
- Bundesministerium für Bildung und Forschung
- National Institutes of Health
- National Human Genome Research Institute (R01HG003143)
- FP7 Ideas: European Research Council (250367)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic and Clinical Aspects of Sex Determination and Chromosomal Abnormalities
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Chromosomal and Genetic Variations
- Keywords
- X inactivation center, XIST, Tsix, topologically associating domains, 3D genome organization, long-range transcriptional regulation, X chromosome inactivation, chromatin interactions, embryonic stem cells, cell differentiation, lamina-associated domains, distal regulatory regions
- MeSH terms
- Animals, Cell Differentiation, Female, Fibroblasts, Gene Expression Regulation, Histones, Male, Methylation, Molecular Sequence Data, Promoter Regions, Genetic, X Chromosome, In Situ Hybridization, Fluorescence, DNA, Intergenic, RNA, Untranslated, Epigenesis, Genetic, X Chromosome Inactivation, Mice, Embryonic Stem Cells, Epigenomics, Transcriptome, RNA, Long Noncoding
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