Disruptions of Topological Chromatin Domains Cause Pathogenic Rewiring of Gene-Enhancer Interactions
Open accessAbstract
Mammalian genomes are organized into megabase-scale topologically associated domains (TADs). We demonstrate that disruption of TADs can rewire long-range regulatory architecture and result in pathogenic phenotypes. We show that distinct human limb malformations are caused by deletions, inversions, or duplications altering the structure of the TAD-spanning WNT6/IHH/EPHA4/PAX3 locus. Using CRISPR/Cas genome editing, we generated mice with corresponding rearrangements. Both in mouse limb tissue and patient-derived fibroblasts, disease-relevant structural changes cause ectopic interactions between promoters and non-coding DNA, and a cluster of limb enhancers normally associated with Epha4 is misplaced relative to TAD boundaries and drives ectopic limb expression of another gene in the locus. This rewiring occurred only if the variant disrupted a CTCF-associated boundary domain. Our results demonstrate the functional importance of TADs for orchestrating gene expression via genome architecture and indicate criteria for predicting the pathogenicity of human structural variants, particularly in non-coding regions of the human genome.
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Loss of TAD insulation between limb-specific enhancers associated with EPHA4 expression and adjacent genes including WNT6 and PAX3 results in their misexpression and abnormal limb development in both mice and humans.
“loss of TAD insulation between limb-specific enhancers associated with EPHA4 expression and a set of adjacent genes, including WNT6 and PAX3, results in their misexpression and abnormal limb development in both mice and humans [446].”
From Transcriptional enhancers and their communication with gene promoters (2021) · cites this paper as [446]
The Results sections on structural changes and enhancer interactions report Pax3 and Wnt6 misexpression in mutant mouse limbs and new contacts with enhancers in the Epha4 TAD. The Discussion section on conservation reports corresponding abnormal chromatin interactions in patient fibroblasts, but does not demonstrate WNT6 or PAX3 misexpression in developing human limbs; it presents the link to human limb phenotypes as a plausible explanation, not an established result. Page numbers were not provided in our copy. (LLM, conf=0.86)
Experimental — accuracy not yet measuredGenomic changes that remove CTCF-associated boundaries permit abnormal enhancer-gene interactions and change gene expression.
“Genomic alterations that remove CTCF-associated boundaries allow aberrant enhancer-gene interactions and alter gene expression17.”
From Insulator dysfunction and oncogene activation in IDH mutant gliomas (2016) · cites this paper as [17]
CRISPR technology has recently made it much more straightforward to delete genomic sequences in the mouse, enabling new insights into enhancer redundancy and consequences of disrupting TADs.
“Second, CRISPR technology has recently made it much more straightforward to delete genomic sequences in the mouse, enabling new insights into aspects such as enhancer redundancy115 and the consequences of disrupting TADs220.”
From Towards a comprehensive catalogue of validated and target-linked human enhancers (2020) · cites this paper as [220]
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 [39]
CTCF mediates enhancer-blocking insulation through the specification of TAD boundaries.
“This observation supports at the genome-wide level the notion that CTCF can mediate enhancer-blocking insulation through the specification of TAD boundaries, in line with previous locus-specific studies (Dowen et al., 2014; Doyle et al., 2014; Lupiáñez et al., 2015; Nora et al., 2012).”
From Targeted Degradation of CTCF Decouples Local Insulation of Chromosome Domains from Genomic Compartmentalization (2017) · cites this paper as Lupiáñez et al., 2015
Boundary disruption has been linked to cancer and diseases of limb development.
“Boundary disruption has recently been linked to cancer and diseases of limb development (Flavahan et al., 2016; Hnisz et al., 2016; Lupianez et al., 2015)”
From Disease-Associated Short Tandem Repeats Co-localize with Chromatin Domain Boundaries (2018) · cites this paper as Lupianez et al., 2015
Recent high-resolution Chromosome-Conformation-Capture sequencing studies have revealed that TAD boundaries are perturbed in rare human limb malformation diseases and certain types of cancers, leading to enhancer miswiring and pathogenic disruption of gene expression.
“Recent high-resolution Chromosome-Conformation-Capture sequencing studies have revealed that TAD boundaries are perturbed in rare human limb malformation diseases (Lupianez et al., 2015) and certain types of cancers (Flavahan et al., 2016; Hnisz et al., 2016), leading to enhancer miswiring and pathogenic disruption of gene expression.”
From Disease-Associated Short Tandem Repeats Co-localize with Chromatin Domain Boundaries (2018) · cites this paper as Lupianez et al., 2015
Domain insulation is important for gene expression and physiology.
“Domain insulation has been shown to be important for gene expression and physiology (Flavahan et al., 2016, Lupiáñez et al., 2015).”
From Multiscale 3D Genome Rewiring during Mouse Neural Development (2017) · cites this paper as Lupiáñez et al., 2015
The integrity of domain structures is important for the proper regulation of genes.
“Therefore, the integrity of the domain structures is important for the proper regulation of genes8–12.”
From Disruption of chromatin folding domains by somatic genomic rearrangements in human cancer (2020) · cites this paper as [9]
Disruption of domain boundaries can result in ectopic interactions between neighboring domains and affect the regulation of nearby genes.
“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 [9]
Loss of a TAD boundary between limb enhancers and the wnt6 gene is sufficient to upregulate wnt6 expression and cause developmental defects in both mice and humans.
“loss of a TAD boundary between limb enhancers and the wnt6 gene is sufficient to upregulate wnt6 expression and cause developmental defects in both mice and humans.28”
From Recent evidence that TADs and chromatin loops are dynamic structures (2018) · cites this paper as [28]
Deletion of a boundary between two TADs causes ectopic contacts between previously insulated loci and can cause aberrant gene expression through improper enhancer-promoter contact.
“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 [28]
Hereditary mutations that invert or delete a TAD boundary at the EPHA4 locus have been linked to limb malformations in humans, and this TAD has a TAD-spanning CTCF-CTCF loop in ES cells, indicating that it is an insulated neighborhood.
“Hereditary mutations that invert or delete a TAD boundary at the EPHA4 locus have recently been linked to limb malformations in humans (Lupianez et al., 2015), and this TAD has a TAD-spanning CTCF-CTCF loop in ES cells, indicating that it is an insulated neighborhood.”
From Insulated Neighborhoods: Structural and Functional Units of Mammalian Gene Control (2016) · cites this paper as Lupianez et al., 2015
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Cites
A 3D Map of the Human Genome at Kilobase Resolution Reveals Principles of Chromatin Looping
Rao, S. S. P., Huntley, M. H., Durand, N. C., Stamenova, E. K., Bochkov, I. D., Robinson, J. T., Sanborn, A. L., Machol, I., Omer, A. D., Lander, E. S., et al. (2014) · Cell · doi:10.1016/j.cell.2014.11.021 · Cited by 9,212 · see citing works
Comprehensive Mapping of Long-Range Interactions Reveals Folding Principles of the Human Genome
Lieberman-Aiden, E., van Berkum, N. L., Williams, L., Imakaev, M., Ragoczy, T., Telling, A., Amit, I., Lajoie, B. R., Sabo, P. J., Dorschner, M. O., et al. (2009) · Science · doi:10.1126/science.1181369 · Cited by 8,898 · see citing works
Topological domains in mammalian genomes identified by analysis of chromatin interactions
Dixon, J. R., Selvaraj, S., Yue, F., Kim, A., Li, Y., Shen, Y., Hu, M., Liu, J. S., & Ren, B. (2012) · Nature · doi:10.1038/nature11082 · Cited by 6,829 · see citing works
DNA targeting specificity of RNA-guided Cas9 nucleases
Hsu, P. D., Scott, D. A., Weinstein, J. A., Ran, F. A., Konermann, S., Agarwala, V., Li, Y., Fine, E. J., Wu, X., Shalem, O., et al. (2013) · Nature Biotechnology · doi:10.1038/nbt.2647 · Cited by 4,741 · see citing works
Spatial partitioning of the regulatory landscape of the X-inactivation centre
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., et al. (2012) · Nature · doi:10.1038/nature11049 · Cited by 2,895 · see citing works
The ENCODE (ENCyclopedia Of DNA Elements) Project
(2004) · Science · doi:10.1126/science.1105136 · Cited by 2,390 · see citing works
St‐Jacques, B., Hammerschmidt, M., & McMahon, A. P. (1999) · Genes & Development · doi:10.1101/gad.13.16.2072 · Cited by 1,742 · see citing works
ChIP-seq accurately predicts tissue-specific activity of enhancers
Visel, A., Blow, M. J., Li, Z., Zhang, T., Akiyama, J. A., Holt, A., Plajzer-Frick, I., Shoukry, M., Wright, C., Chen, F., et al. (2009) · Nature · doi:10.1038/nature07730 · Cited by 1,639 · see citing works
Self-citationA high-resolution map of the three-dimensional chromatin interactome in human cells
Jin, F., Li, Y., Dixon, J. R., Selvaraj, S., Ye, Z., Lee, A. Y., Yen, C.-A., Schmitt, A. D., Espinoza, C. A., & Ren, B. (2013) · Nature · doi:10.1038/nature12644 · Cited by 1,208 · see citing works
Structural Variation in the Human Genome and its Role in Disease
Stankiewicz, P., & Lupski, J. R. (2010) · Annual Review of Medicine · doi:10.1146/annurev-med-100708-204735 · Cited by 1,201 · see citing works
VISTA Enhancer Browser—a database of tissue-specific human enhancers
Visel, A., Minovitsky, S., Dubchak, I., & Pennacchio, L. A. (2007) · Nucleic Acids Research · doi:10.1093/nar/gkl822 · Cited by 1,080 · see citing works
Self-citationGenomic views of distant-acting enhancers
Visel, A., Rubin, E. M., & Pennacchio, L. A. (2009) · Nature · doi:10.1038/nature08451 · Cited by 610 · see citing works
Self-citationTopology of mammalian developmental enhancers and their regulatory landscapes
de Laat, W., & Duboule, D. (2013) · Nature · doi:10.1038/nature12753 · Cited by 521 · see citing works
Regulation of Pax-3 expression in the dermomyotome and its role in muscle development
Goulding, M., Lumsden, A., & Paquette, A. J. (1994) · Development · doi:10.1242/dev.120.4.957 · Cited by 496 · see citing works
Enhancer–core-promoter specificity separates developmental and housekeeping gene regulation
Zabidi, M. A., Arnold, C. D., Schernhuber, K., Pagani, M., Rath, M., Frank, O., & Stark, A. (2015) · Nature · doi:10.1038/nature13994 · Cited by 471 · see citing works
Disruption of a long-range cis-acting regulator for Shh causes preaxial polydactyly
Lettice, L. A., Horikoshi, T., Heaney, S. J. H., van Baren, M. J., van der Linde, H. C., Breedveld, G. J., Joosse, M., Akarsu, N. A., Oostra, B. A., Endo, N., et al. (2002) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.112212199 · Cited by 458 · see citing works
Insulator function and topological domain border strength scale with architectural protein occupancy
Bortle, K. V., Nichols, M. H., Li, L., Ong, C., Takenaka, N., Qin, Z. S., & Corces, V. G. (2014) · Genome biology · doi:10.1186/gb-2014-15-5-r82 · Cited by 294 · see citing works
Helmbacher, F., Schneider‐Maunoury, S., Topilko, P., Tiret, L., & Charnay, P. (2000) · Development · doi:10.1242/dev.127.15.3313 · Cited by 262 · see citing works
4C Technology: Protocols and Data Analysis
van de Werken, H. J. G., de Vree, P. J. P., Splinter, E., Holwerda, S. J. B., Klous, P., de Wit, E., & de Laat, W. L. (2012) · Methods in enzymology on CD-ROM/Methods in enzymology · doi:10.1016/b978-0-12-391938-0.00004-5 · Cited by 240 · see citing works
Deletions, Inversions, Duplications: Engineering of Structural Variants using CRISPR/Cas in Mice
Kraft, K., Geuer, S., Will, A. J., Chan, W. L., Paliou, C., Borschiwer, M., Harabula, I., Wittler, L., Franke, M., Ibrahim, D. M., et al. (2015) · Cell Reports · doi:10.1016/j.celrep.2015.01.016 · Cited by 216 · see citing works
Self-citationImpacts of Variation in the Human Genome on Gene Regulation
Haraksingh, R., & Snyder, M. P. (2013) · Journal of Molecular Biology · doi:10.1016/j.jmb.2013.07.015 · Cited by 162 · see citing works
Deletions of chromosomal regulatory boundaries are associated with congenital disease
Ibn-Salem, J., Köhler, S., Love, M. I., Chung, H.-R., Huang, N., Hurles, M. E., Haendel, M., Washington, N. L., Smedley, D., Mungall, C. J., et al. (2014) · Genome Biology · doi:10.1186/s13059-014-0423-1 · Cited by 143 · see citing works
Self-citationCotney, J. L., Leng, J., Oh, S., DeMare, L. E., Reilly, S. K., Gerstein, M., & Noonan, J. P. (2012) · Genome Research · doi:10.1101/gr.129817.111 · Cited by 124 · see citing works
Swaminathan, G. J., Bragin, E., Chatzimichali, E., Corpas, M., Bevan, A. P., Wright, C. F., Carter, N. P., Hurles, M. E., & Firth, H. V. (2012) · Human Molecular Genetics · doi:10.1093/hmg/dds362 · Cited by 78 · see citing works
Structural variations, the regulatory landscape of the genome and their alteration in human disease.
Spielmann, M., & Mundlos, S. (2013) · Bioessays · doi:10.1002/bies.201200178 · Cited by 69 · see citing works
Self-citationTsujimura, T., Klein, F. A., Langenfeld, K., Glaser, J., Huber, W. K., & Spitz, F. (2015) · PLoS Genetics · doi:10.1371/journal.pgen.1004897 · Cited by 64 · see citing works
Artus, J., & Hadjantonakis, A. (2010) · Methods in molecular biology · doi:10.1007/978-1-60761-974-1_3 · Cited by 52 · see citing works
Impact of copy number variations (CNVs) on long-range gene regulation at the HoxD locus
Montavon, T., Thevenet, L., & Duboule, D. (2012) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1217659109 · Cited by 38 · see citing works
Babbs, C., Furniss, D., Morriss‐Kay, G. M., & Wilkie, A. O. M. (2008) · Mechanisms of Development · doi:10.1016/j.mod.2008.01.001 · Cited by 31 · see citing works
Ectodermal Wnt6 is an early negative regulator of limb chondrogenesis in the chicken embryo
Geetha‐Loganathan, P., Nimmagadda, S., Christ, B., Huang, R., & Scaal, M. (2010) · BMC Developmental Biology · doi:10.1186/1471-213x-10-32 · Cited by 26 · see citing works
A large duplication involving the IHH locus mimics acrocallosal syndrome
Yüksel‐Apak, M., Bögershausen, N., Pawlik, B., Li, Y., Apak, S., Uyguner, Z. O., Milz, E., Nürnberg, G., Karaman, B., Gülgören, A., et al. (2012) · European Journal of Human Genetics · doi:10.1038/ejhg.2011.250 · Cited by 17 · see citing works
Self-citationF‐syndrome (F‐form of acro‐pectoro‐vertebral dysplasia): Report on a second family
Camera, G., Camera, A., Pozzolo, S., et al. (1995) · American Journal of Medical Genetics · doi:10.1002/ajmg.1320570322 · Cited by 8 · see citing works
Acropectorovertebral dysgenesis (F syndrome) maps to chromosome 2q36
Thiele, H. (2004) · Journal of Medical Genetics · doi:10.1136/jmg.2003.014894 · Cited by 8 · see citing works
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Formation of chromosomal domains by loop extrusion
Fudenberg, G., Imakaev, M., Lu, C., Goloborodko, A., Abdennur, N., & Mirny, L. A. (2016) · Cell Reports · doi:10.1016/j.celrep.2016.04.085 · Cited by 2,003 · see citing works
Cohesin Loss Eliminates All Loop Domains
Rao, S. S. P., Huang, S.-C., Glenn St Hilaire, B., Engreitz, J. M., Perez, E. M., Kieffer-Kwon, K.-R., Sanborn, A. L., Johnstone, S. E., Bascom, G. D., Bochkov, I. D., et al. (2017) · Cell · doi:10.1016/j.cell.2017.09.026 · Cited by 1,883 · see citing works
Nora, E. P., Goloborodko, A., Valton, A.-L., Gibcus, J. H., Uebersohn, A., Abdennur, N., Dekker, J., Mirny, L. A., & Bruneau, B. G. (2017) · Cell · doi:10.1016/j.cell.2017.05.004 · Cited by 1,709 · see citing works
Insulator dysfunction and oncogene activation in IDH mutant gliomas
Flavahan, W. A., Drier, Y., Liau, B. B., Gillespie, S. M., Venteicher, A. S., Stemmer-Rachamimov, A. O., Suvà, M. L., & Bernstein, B. E. (2016) · Nature · doi:10.1038/nature16490 · Cited by 1,288 · see citing works
Multiscale 3D Genome Rewiring during Mouse Neural Development
Bonev, B., Mendelson Cohen, N., Szabo, Q., Fritsch, L., Papadopoulos, G. L., Lubling, Y., Xu, X., Lv, X., Hugnot, J.-P., Tanay, A., et al. (2017) · Cell · doi:10.1016/j.cell.2017.09.043 · Cited by 1,338 · see citing works
Two independent modes of chromatin organization revealed by cohesin removal
Schwarzer, W., Abdennur, N., Goloborodko, A., Pekowska, A., Fudenberg, G., Loe-Mie, Y., Fonseca, N. A., Huber, W., Haering, C. H., Mirny, L., et al. (2017) · Nature · doi:10.1038/nature24281 · Cited by 1,196 · see citing works
Long-range enhancer–promoter contacts in gene expression control
Schoenfelder, S., & Fraser, P. (2019) · Nature Reviews Genetics · doi:10.1038/s41576-019-0128-0 · Cited by 1,102 · see citing works
The 3D Genome as Moderator of Chromosomal Communication
Dekker, J., & Mirny, L. (2016) · Cell · doi:10.1016/j.cell.2016.02.007 · Cited by 937 · see citing works
Genetic studies in intellectual disability and related disorders
Vissers, L. E. L. M., Gilissen, C., & Veltman, J. A. (2016) · Nature Reviews Genetics · doi:10.1038/nrg3999 · Cited by 761 · see citing works
Formation of new chromatin domains determines pathogenicity of genomic duplications
Franke, M., Ibrahim, D. M., Andrey, G., Schwarzer, W., Heinrich, V., Schöpflin, R., Kraft, K., Kempfer, R., Jerković, I., Chan, W.-L., et al. (2016) · Nature · doi:10.1038/nature19800 · Cited by 673 · see citing works
Self-citationThe Key Role of Epigenetics in Human Disease Prevention and Mitigation
Feinberg, A. P. (2018) · New England Journal of Medicine · doi:10.1056/nejmra1402513 · Cited by 638 · see citing works
CTCF and cohesin regulate chromatin loop stability with distinct dynamics
Hansen, A. S., Pustova, I., Cattoglio, C., Tjian, R., & Darzacq, X. (2017) · eLife · doi:10.7554/elife.25776 · Cited by 613 · see citing works
The Energetics and Physiological Impact of Cohesin Extrusion
Vian, L., Pękowska, A., Rao, S. S. P., Kieffer-Kwon, K.-R., Jung, S., Baranello, L., Huang, S.-C., El Khattabi, L., Dose, M., Pruett, N., et al. (2018) · Cell · doi:10.1016/j.cell.2018.03.072 · Cited by 581 · see citing works
Integrative detection and analysis of structural variation in cancer genomes
Dixon, J. R., Xu, J., Dileep, V., Zhan, Y., Song, F., Le, V. T., Yardımcı, G. G., Chakraborty, A., Bann, D. V., Wang, Y., et al. (2018) · Nature Genetics · doi:10.1038/s41588-018-0195-8 · Cited by 452 · see citing works
Nonlinear control of transcription through enhancer–promoter interactions
Zuin, J., Roth, G., Zhan, Y., Cramard, J., Redolfi, J., Piskadlo, E., Mach, P., Kryzhanovska, M., Tihanyi, G., Kohler, H., et al. (2022) · Nature · doi:10.1038/s41586-022-04570-y · Cited by 415 · see citing works
Insulated Neighborhoods: Structural and Functional Units of Mammalian Gene Control
Hnisz, D., Day, D. S., & Young, R. A. (2016) · Cell · doi:10.1016/j.cell.2016.10.024 · Cited by 420 · see citing works
Weischenfeldt, J., Dubash, T., Drainas, A. P., Mardin, B. R., Chen, Y., Stütz, A. M., Waszak, S. M., Bosco, G., Halvorsen, A. R., Raeder, B., et al. (2017) · Nature Genetics · doi:10.1038/ng.3722 · Cited by 404 · see citing works
Hsieh, T.-H. S., Cattoglio, C., Slobodyanyuk, E., Hansen, A. S., Darzacq, X., & Tjian, R. (2022) · Nature Genetics · doi:10.1038/s41588-022-01223-8 · Cited by 406 · see citing works
Towards a comprehensive catalogue of validated and target-linked human enhancers
Gasperini, M., Tome, J. M., & Shendure, J. (2020) · Nature Reviews Genetics · doi:10.1038/s41576-019-0209-0 · Cited by 396 · see citing works
Redin, C., Brand, H., Collins, R. L., Kammin, T., Mitchell, E., Hodge, J. C., Hanscom, C., Pillalamarri, V., Seabra, C. M., Abbott, M.-A., et al. (2017) · Nature Genetics · doi:10.1038/ng.3720 · Cited by 334 · see citing works
Highly rearranged chromosomes reveal uncoupling between genome topology and gene expression
Ghavi-Helm, Y., Jankowski, A., Meiers, S., Viales, R. R., Korbel, J. O., & Furlong, E. E. M. (2019) · Nature Genetics · doi:10.1038/s41588-019-0462-3 · Cited by 354 · see citing works
YY1 and CTCF orchestrate a 3D chromatin looping switch during early neural lineage commitment
Beagan, J. A., Duong, M. T., Titus, K. R., Zhou, L., Cao, Z., Ma, J., Lachanski, C. V., Gillis, D. R., & Phillips-Cremins, J. E. (2017) · Genome Research · doi:10.1101/gr.215160.116 · Cited by 299 · see citing works
“…of TADs (Dixon et al. 2012; Nora et al. 2012), and deletion or inversion of these motifs can perturb domain boundaries and disrupt nearby gene expression (Dowen et al. 2014; de Wit et al. 2015; Guo et al. 2015; Lupiáñez et al. 2015; Narendra et al. 2015; Sanborn et al. 2015; Flavahan et al. 2016).”
InfluentialDisruption of chromatin folding domains by somatic genomic rearrangements in human cancer
Akdemir, K. C., Le, V. T., Chandran, S., Li, Y., Verhaak, R. G., Beroukhim, R., Campbell, P. J., Chin, L., Dixon, J. R., Futreal, P. A., et al. (2020) · Nature Genetics · doi:10.1038/s41588-019-0564-y · Cited by 283 · see citing works
Self-citationDistinct Classes of Chromatin Loops Revealed by Deletion of an RNA-Binding Region in CTCF
Hansen, A. S., Hsieh, T.-H. S., Cattoglio, C., Pustova, I., Saldaña-Meyer, R., Reinberg, D., Darzacq, X., & Tjian, R. (2019) · Molecular Cell · doi:10.1016/j.molcel.2019.07.039 · Cited by 279 · see citing works
Recent evidence that TADs and chromatin loops are dynamic structures
Hansen, A. S., Cattoglio, C., Darzacq, X., & Tjian, R. (2018) · Nucleus · doi:10.1080/19491034.2017.1389365 · Cited by 266 · see citing works
Disease-Associated Short Tandem Repeats Co-localize with Chromatin Domain Boundaries
Sun, J. H., Zhou, L., Emerson, D. J., Phyo, S. A., Titus, K. R., Gong, W., Gilgenast, T. G., Beagan, J. A., Davidson, B. L., Tassone, F., et al. (2018) · Cell · doi:10.1016/j.cell.2018.08.005 · Cited by 249 · see citing works
“Recent high-resolution chromosomeconformation-capture sequencing studies have revealed that TAD boundaries are perturbed in rare human limb malformation diseases (Lupiáñez et al., 2015) and certain types of cancers (Flavahan et al.”
BackgroundDynamic Rewiring of Promoter-Anchored Chromatin Loops during Adipocyte Differentiation
Siersbæk, R., Madsen, J. G. S., Javierre, B. M., Nielsen, R., Bagge, E. K., Cairns, J., Wingett, S. W., Traynor, S., Spivakov, M., Fraser, P., et al. (2017) · Molecular Cell · doi:10.1016/j.molcel.2017.04.010 · Cited by 243 · see citing works
Transcription in Living Cells: Molecular Mechanisms of Bursting
Rodriguez, J., & Larson, D. R. (2020) · Annual Review of Biochemistry · doi:10.1146/annurev-biochem-011520-105250 · Cited by 224 · see citing works
Miron, E., Oldenkamp, R., Brown, J. M., Pinto, D. M. S., Xu, C. S., Faria, A. R., Shaban, H. A., Rhodes, J. D. P., Innocent, C., de Ornellas, S., et al. (2020) · Science Advances · doi:10.1126/sciadv.aba8811 · Cited by 200 · see citing works
Evaluation of chromatin accessibility in prefrontal cortex of individuals with schizophrenia
Bryois, J., Garrett, M. E., Song, L., Safi, A., Giusti-Rodriguez, P., Johnson, G. D., Shieh, A. W., Buil, A., Fullard, J. F., Roussos, P., et al. (2018) · Nature Communications · doi:10.1038/s41467-018-05379-y · Cited by 167 · see citing works
Enhancer selectivity in space and time: from enhancer–promoter interactions to promoter activation
Yang, J. H., & Hansen, A. S. (2024) · Nature Reviews Molecular Cell Biology · doi:10.1038/s41580-024-00710-6 · Cited by 191 · see citing works
Huang, H., Zhu, Q., Jussila, A., Han, Y., Bintu, B., Kern, C., Conte, M., Zhang, Y., Bianco, S., Chiariello, A. M., et al. (2021) · Nature Genetics · doi:10.1038/s41588-021-00863-6 · Cited by 187 · see citing works
Cohesin Disrupts Polycomb-Dependent Chromosome Interactions in Embryonic Stem Cells
Rhodes, J. D. P., Feldmann, A., Hernández-Rodríguez, B., Díaz, N., Brown, J. M., Fursova, N. A., Blackledge, N. P., Prathapan, P., Dobrinic, P., Huseyin, M. K., et al. (2020) · Cell Reports · doi:10.1016/j.celrep.2019.12.057 · Cited by 187 · see citing works
Sequence-based modeling of three-dimensional genome architecture from kilobase to chromosome scale
Zhou, J. (2022) · Nature Genetics · doi:10.1038/s41588-022-01065-4 · Cited by 177 · see citing works
How subtle changes in 3D structure can create large changes in transcription
Xiao, J. Y., Hafner, A., & Boettiger, A. N. (2021) · eLife · doi:10.7554/elife.64320 · Cited by 162 · see citing works
Chromosome organization by one-sided and two-sided loop extrusion
Banigan, E. J., van den Berg, A. A., Brandão, H. B., Marko, J. F., & Mirny, L. A. (2020) · eLife · doi:10.7554/elife.53558 · Cited by 146 · see citing works
Radiation-induced DNA damage and repair effects on 3D genome organization
Sanders, J. T., Freeman, T. F., Xu, Y., Golloshi, R., Stallard, M. A., Hill, A. M., San Martin, R., Balajee, A. S., & McCord, R. P. (2020) · Nature Communications · doi:10.1038/s41467-020-20047-w · Cited by 134 · see citing works
Chromosomal contacts connect loci associated with autism, BMI and head circumference phenotypes
2p15 Consortium, Loviglio, M. N., 16p11.2 Consortium, Leleu, M., Männik, K., Passeggeri, M., Giannuzzi, G., van der Werf, I., Waszak, S. M., Zazhytska, M., et al. (2017) · Molecular Psychiatry · doi:10.1038/mp.2016.84 · Cited by 118 · see citing works
Aljahani, A., Hua, P., Karpinska, M. A., Quililan, K., Davies, J. O. J., & Oudelaar, A. M. (2022) · Nature Communications · doi:10.1038/s41467-022-29696-5 · Cited by 121 · see citing works
Large-scale chromatin reorganization reactivates placenta-specific genes that drive cellular aging
Liu, Z., Ji, Q., Ren, J., Yan, P., Wu, Z., Wang, S., Sun, L., Wang, Z., Li, J., Sun, G., et al. (2022) · Developmental Cell · doi:10.1016/j.devcel.2022.05.004 · Cited by 109 · see citing works
Systematic analysis of intrinsic enhancer-promoter compatibility in the mouse genome
Martinez-Ara, M., Comoglio, F., van Arensbergen, J., & van Steensel, B. (2022) · Molecular Cell · doi:10.1016/j.molcel.2022.04.009 · Cited by 101 · see citing works
Jost, D., & Vaillant, C. (2018) · Nucleic Acids Research · doi:10.1093/nar/gky009 · Cited by 84 · see citing works
Identification of copy number variations and translocations in cancer cells from Hi-C data
Chakraborty, A., & Ay, F. (2018) · Bioinformatics · doi:10.1093/bioinformatics/btx664 · Cited by 94 · see citing works
Human evolution: the non-coding revolution
Franchini, L. F., & Pollard, K. S. (2017) · BMC Biology · doi:10.1186/s12915-017-0428-9 · Cited by 90 · see citing works
Gain of CTCF-Anchored Chromatin Loops Marks the Exit from Naive Pluripotency
Pękowska, A., Klaus, B., Xiang, W., Severino, J., Daigle, N., Klein, F. A., Oleś, M., Casellas, R., Ellenberg, J., Steinmetz, L. M., et al. (2018) · Cell Systems · doi:10.1016/j.cels.2018.09.003 · Cited by 74 · see citing works
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
Brown, J. M., Roberts, N. A., Graham, B., Waithe, D., Lagerholm, C., Telenius, J. M., De Ornellas, S., Oudelaar, A. M., Scott, C., Szczerbal, I., et al. (2018) · Nature Communications · doi:10.1038/s41467-018-06248-4 · Cited by 72 · see citing works
Nonlinear control of transcription through enhancer-promoter interactions
Zuin, J., Roth, G., Zhan, Y., Cramard, J., Redolfi, J., Piskadlo, E., Mach, P., Kryzhanovska, M., Tihanyi, G., Kohler, H., et al. (2021) · doi:10.1101/2021.04.22.440891 · Cited by 67 · see citing works
Crossed wires: 3D genome misfolding in human disease
Norton, H. K., & Phillips-Cremins, J. E. (2017) · Journal of Cell Biology · doi:10.1083/jcb.201611001 · Cited by 57 · see citing works
Narducci, D. N., & Hansen, A. S. (2025) · Molecular Cell · doi:10.1016/j.molcel.2024.11.032 · Cited by 25 · see citing works
Genome-wide absolute quantification of chromatin looping
Jusuf, J. M., Yang, J. H., Toppen, J., Grosse-Holz, S., Gabriele, M., Mach, P., Flyamer, I. M., Zechner, C., Giorgetti, L., Mirny, L. A., et al. (2026) · Nature Structural & Molecular Biology · doi:10.1038/s41594-026-01819-2 · Cited by 22 · see citing works
“Disruption of both types of looping has been shown to cause aberrant gene regulation and lead to disease 11–20 .”
Chakraborty, S., Wenzlitschke, N., Anderson, M. J., Eraso, A., Baudic, M., Thompson, J. J., Evans, A. A., Shatford-Adams, L. M., Chari, R., Awasthi, P., et al. (2025) · Developmental Cell · doi:10.1016/j.devcel.2025.02.002 · Cited by 22 · see citing works
Phenotypic subregions within the split-hand/foot malformation 1 locus
Rasmussen, M. B., Kreiborg, S., Jensen, P., Bak, M., Mang, Y., Lodahl, M., Budtz-Jørgensen, E., Tommerup, N., Tranebjærg, L., & Rendtorff, N. D. (2016) · Human Genetics · doi:10.1007/s00439-016-1635-0 · Cited by 18 · see citing works
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
Between form and function: the complexity of genome folding
Oudelaar, A. M., Hanssen, L. L. P., Hardison, R. C., Kassouf, M. T., Hughes, J. R., & Higgs, D. R. (2017) · Human Molecular Genetics · doi:10.1093/hmg/ddx306 · Cited by 16 · see citing works
Evaluation of chromatin accessibility in prefrontal cortex of schizophrenia cases and controls
Bryois, J., Garrett, M. E., Song, L., Safi, A., Giusti-Rodriguez, P., Johnson, G. D., Demur, A. B., Fullard, J. F., Roussos, P., Sklar, P., et al. (2017) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/141986 · Cited by 7 · see citing works
CRISPR-Mediated Reorganization of Chromatin Loop Structure
Morgan, S. L., Chang, E. Y., Mariano, N. C., Bermudez, A., Arruda, N. L., Wu, F., Luo, Y., Shankar, G., Huynh, S. K., Huang, C.-C., et al. (2018) · Journal of Visualized Experiments · doi:10.3791/57457 · Cited by 7 · see citing works
Live-cell imaging of enhancer-promoter dynamics reveals transient contact-driven gene activation
Yang, J. H., Pinholt, H. D., Toppen, J., Huseyin, M. K., Jusuf, J. M., Katsifis, C. C., Kæstel-Hansen, J., Mirny, L. A., Zechner, C., & Hansen, A. S. (2026) · doi:10.64898/2026.06.21.733446 · Cited by 3 · see citing works
Topological Approaches in Animal Comparative Genomics
Schultz, D. T., & Simakov, O. (2026) · Annual Review of Animal Biosciences · doi:10.1146/annurev-animal-030424-084541 · Cited by 1 · see citing works
Choppavarapu, L., Nosirov, B., Kahn, M., & Jin, V. X. (2026) · Cancers · doi:10.3390/cancers18213416
- Authors
- Lupiáñez, D. G., Kraft, K., Heinrich, V., Krawitz, P., Brancati, F., Klopocki, E., Horn, D., Kayserili, H., Opitz, J. M., Laxova, R., Santos-Simarro, F., Gilbert-Dussardier, B., Wittler, L., Borschiwer, M., Haas, S. A., Osterwalder, M., Franke, M., Timmermann, B., Hecht, J., Spielmann, M., Visel, A., & Mundlos, S.
- Affiliations
- Max Planck Institute for Molecular Genetics (DE)
- Charité – Universitätsmedizin Berlin (DE)
- Policlinico Tor Vergata (IT)
- University of Würzburg (DE)
- Istanbul University (TR)
- University of Utah (US)
- Lawrence Berkeley National Laboratory (US)
- Berlin-Brandenburger Centrum für Regenerative Therapien (DE)
- Corresponding author
- Mundlos, Stefan
- ORCID
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2015-05
- Volume
- 161
- Issue
- 5
- Pages
- 1012-1025
- ISSN
- 0092-8674 (ISSN-L)
- PMC
- PMC4791538
- OpenAlex
- W1859117663
- Cited by
- 2,132
- References
- 33
- Citations by year
- 2026: 132 · 2025: 158 · 2024: 182 · 2023: 195 · 2022: 214 · 2021: 246 · 2020: 226 · 2019: 226 · 2018: 196 · 2017: 175 · 2016: 130 · 2015: 47 · 2012: 1
- FWCI
- 78.84
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- LA Referencia (Red Federada de Repositorios Institucionales de Publicaciones Científicas) (submittedVersion, other-oa)
- MDC Repository (Max-Delbrueck-Center for Molecular Medicine) (submittedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- OSTI OAI (U.S. Department of Energy Office of Scientific and Technical Information) (submittedVersion)
- MPG.PuRe (Max Planck Society) (submittedVersion, other-oa)
- Archivio Istituzionale della Ricerca - Università degli Studi dell Aquila (submittedVersion)
- Funders
- Fundación Alfonso Martín Escudero
- Deutsche Forschungsgemeinschaft
- Berlin Institute for Health
- Max Planck Foundation
- Swiss National Science Foundation
- NIH (R01HG003988, U54HG006997, U01DE024427)
- Department of Energy (DE-AC02-05CH11231)
- University of California
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomic variations and chromosomal abnormalities
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Chromatin Remodeling and Cancer
- Keywords
- topologically associating domains, chromatin organization, limb malformations, structural variants, ectopic expression, pathogenicity prediction, mouse models of human disease, patient-derived fibroblasts
- MeSH terms
- Animals, Disease Models, Animal, Enhancer Elements, Genetic, Extremities, Gene Expression Regulation, Humans, Promoter Regions, Genetic, Limb Deformities, Congenital, RNA, Untranslated, Receptor, EphA4, Mice
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