Evolutionary comparison reveals that diverging CTCF sites are signatures of ancestral topological associating domains borders
Open accessAbstract
Significance: Mammalian chromatin is compartmentalized in topologically associating domains (TADs), genomic regions within which sequences preferentially contact each other. This organization has been proposed to be essential to organize the regulatory information contained in mammalian genomes. We show that Six homeobox genes, essential developmental regulators organized in gene clusters across different animal phyla, share a deeply conserved chromatin organization formed by two abutting TADs that predates the Cambrian explosion. This organization is required to generate separate regulatory landscapes for neighboring genes within the cluster, resulting in very different gene expression patterns. Finally, we show that this extremely conserved 3D architecture is associated with a characteristic arrangement of CCCTC-binding factor (CTCF) binding sites in diverging orientations, revealing a genome-wide conserved signature for TAD borders.
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Effective chromatin boundaries are formed by two directly adjacent divergent CTCF binding sites.
“It has been suggested that effective chromatin boundaries are formed by two directly adjacent divergent CTCF binding sites30.”
From Tissue-specific CTCF-cohesin-mediated chromatin architecture delimits enhancer interactions and function in vivo (2017) · cites this paper as [30]
The CTCF DNA binding motif is asymmetric and directional, and the CTCF anchors of >90% of loop domains occur in a convergent orientation.
“This and other studies have noted that the DNA binding motif of CTCF is asymmetric and thus directional, and the CTCF anchors of >90% the loop domains occur in a convergent orientation (de Wit et al., 2015; Gomez-Marin et al., 2015; Guo et al., 2015; Ji et al., 2016; Vietri Rudan et al., 2015).”
From Insulated Neighborhoods: Structural and Functional Units of Mammalian Gene Control (2016) · cites this paper as Gomez-Marin et al., 2015
Cites
An integrated encyclopedia of DNA elements in the human genome
The ENCODE Project Consortium (2012) · Nature · doi:10.1038/nature11247 · Cited by 18,072 · see citing works
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
Capturing Chromosome Conformation
Dekker, J., Rippe, K., Dekker, M., & Kleckner, N. (2002) · Science · doi:10.1126/science.1067799 · Cited by 3,652 · 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
Three-dimensional folding and functional organization principles of the Drosophila genome
Sexton, T., Yaffe, E., Kenigsberg, E., Bantignies, F., Leblanc, B., Hoichman, M., Parrinello, H., Tanay, A., & Cavalli, G. (2012) · Cell · doi:10.1016/j.cell.2012.01.010 · Cited by 1,983 · see citing works
Single-cell Hi-C reveals cell-to-cell variability in chromosome structure
Nagano, T., Lubling, Y., Stevens, T. J., Schoenfelder, S., Yaffe, E., Dean, W., Laue, E. D., Tanay, A., & Fraser, P. (2013) · Nature · doi:10.1038/nature12593 · Cited by 1,589 · see citing works
Modification of Enhancer Chromatin: What, How, and Why?
Calo, E., & Wysocka, J. (2013) · Molecular Cell · doi:10.1016/j.molcel.2013.01.038 · Cited by 1,457 · see citing works
Obesity-associated variants within FTO form long-range functional connections with IRX3
Smemo, S., Tena, J. J., Kim, K.-H., Gamazon, E. R., Sakabe, N. J., Gómez-Marín, C., Aneas, I., Credidio, F. L., Sobreira, D. R., Wasserman, N. F., et al. (2014) · Nature · doi:10.1038/nature13138 · Cited by 1,219 · 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
CTCF: an architectural protein bridging genome topology and function
Ong, C., & Corces, V. G. (2014) · Nature Reviews Genetics · doi:10.1038/nrg3663 · Cited by 1,044 · see citing works
Quantitative analysis of chromosome conformation capture assays (3C-qPCR)
Hagège, H., Klous, P., Braem, C., Splinter, E., Dekker, J., Cathala, G., de Laat, W., & Forné, T. (2007) · Nature Protocols · doi:10.1038/nprot.2007.243 · Cited by 720 · see citing works
Enhancer loops appear stable during development and are associated with paused polymerase
Ghavi-Helm, Y., Klein, F. A., Pakozdi, T., Ciglar, L., Noordermeer, D., Huber, W., & Furlong, E. E. M. (2014) · Nature · doi:10.1038/nature13417 · Cited by 536 · see citing works
Comparative genomics provides evidence for an ancient genome duplication event in fish
Taylor, J. S., de Peer, Y. V., Braasch, I., & Meyer, A. (2001) · Philosophical Transactions of the Royal Society B Biological Sciences · doi:10.1098/rstb.2001.0975 · Cited by 532 · see citing works
Topology 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
Hughes, J. R., Roberts, N., McGowan, S., Hay, D., Giannoulatou, E., Lynch, M., De Gobbi, M., Taylor, S., Gibbons, R., & Higgs, D. R. (2014) · Nature Genetics · doi:10.1038/ng.2871 · Cited by 461 · see citing works
Detection of functional DNA motifs via statistical over-representation
Frith, M. C. (2004) · Nucleic Acids Research · doi:10.1093/nar/gkh299 · Cited by 424 · see citing works
A Switch Between Topological Domains Underlies HoxD Genes Collinearity in Mouse Limbs
Andrey, G., Montavon, T., Mascrez, B., Gonzãlez, F., Noordermeer, D., Leleu, M., Trono, D., Spitz, F., & Duboule, D. (2013) · Science · doi:10.1126/science.1234167 · Cited by 409 · see citing works
The Dynamic Architecture of Hox Gene Clusters
Noordermeer, D., Leleu, M., Splinter, E., Rougemont, J., de Laat, W. L., & Duboule, D. (2011) · Science · doi:10.1126/science.1207194 · Cited by 391 · see citing works
Jowett, T., & Lettice, L. A. (1994) · Trends in Genetics · doi:10.1016/0168-9525(94)90220-8 · Cited by 386 · see citing works
Transposon-mediated BAC transgenesis in zebrafish
Suster, M. L., Abe, G., Schouw, A., & Kawakami, K. (2011) · Nature Protocols · doi:10.1038/nprot.2011.416 · Cited by 226 · see citing works
Splinter, E., de Wit, E., van de Werken, H. J. G., Klous, P., & de Laat, W. L. (2012) · Methods · doi:10.1016/j.ymeth.2012.04.009 · Cited by 224 · see citing works
Buenrostro, J. D., Araya, C. L., Chircus, L. M., Layton, C. J., Chang, H. Y., Snyder, M. P., & Greenleaf, W. J. (2014) · Nature Biotechnology · doi:10.1038/nbt.2880 · Cited by 214 · see citing works
Gallardo, M. E., López-Rı́os, J., Fernaud-Espinosa, I., et al. (1999) · Genomics · doi:10.1006/geno.1999.5916 · Cited by 175 · see citing works
Six3 demarcates the anterior-most developing brain region in bilaterian animals
Steinmetz, P. R. H., Urbach, R., Posnien, N., Eriksson, J., Kostyuchenko, R. P., Brena, C., Guy, K., Akam, M. E., Bucher, G., & Arendt, D. (2010) · EvoDevo · doi:10.1186/2041-9139-1-14 · Cited by 172 · see citing works
Rapid BAC selection fortol2-mediated transgenesis in zebrafish
Bussmann, J., & Schulte‐Merker, S. (2011) · Development · doi:10.1242/dev.068080 · Cited by 172 · see citing works
Irimia, M., Tena, J. J., Alexis, M. S., Fernandez-Miñan, A., Maeso, I., Bogdanović, O., de la Calle-Mustienes, E., Roy, S. W., Gómez-Skarmeta, J. L., & Fraser, H. B. (2012) · Genome Research · doi:10.1101/gr.139725.112 · Cited by 146 · see citing works
Self-citationTemporal dynamics and developmental memory of 3D chromatin architecture at Hox gene loci
Noordermeer, D., Leleu, M., Schorderet, P., Joye, E., Chabaud, F., & Duboule, D. (2014) · eLife · doi:10.7554/elife.02557 · Cited by 142 · see citing works
Stadhouders, R., Kolovos, P., Brouwer, R. W. W., Zuin, J., van den Heuvel, A., Kockx, C. E. M., Palstra, R.-J. T. S., Wendt, K. S., Grosveld, F. G., van IJcken, W. F. J., et al. (2013) · Nature Protocols · doi:10.1038/nprot.2013.018 · Cited by 141 · see citing works
Odd-skipped genes encode repressors that control kidney development
Tena, J. J., Neto, A., de la Calle‐Mustienes, E., Brás‐Pereira, C., Casares, F., & Gómez-Skármeta, J. L. (2006) · Developmental Biology · doi:10.1016/j.ydbio.2006.08.063 · Cited by 134 · see citing works
Self-citationDeep conservation of wrist and digit enhancers in fish
Gehrke, A. R., Schneider, I., de la Calle‐Mustienes, E., Tena, J. J., Gómez-Marín, C., Chandran, M., Nakamura, T., Braasch, I., Postlethwait, J. H., Gómez-Skármeta, J. L., et al. (2014) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1420208112 · Cited by 133 · see citing works
Self-citationSummerbell, D., Ashby, P. R., Coutelle, O., et al. (2000) · Development · doi:10.1242/dev.127.17.3745 · Cited by 131 · see citing works
Ransick, A., Ernst, S. G., Britten, R. J., & Davidson, E. H. (1993) · Mechanisms of Development · doi:10.1016/0925-4773(93)90001-e · Cited by 128 · see citing works
The evolution of nervous system patterning: insights from sea urchin development
Angerer, L. M., Yaguchi, S., Angerer, R. C., & Burke, R. D. (2011) · Development · doi:10.1242/dev.058172 · Cited by 117 · see citing works
The sea urchin animal pole domain is a Six3-dependent neurogenic patterning center
Zheng, W., Yaguchi, J., Yaguchi, S., Angerer, R. C., & Angerer, L. M. (2009) · Development · doi:10.1242/dev.032300 · Cited by 107 · see citing works
Li, Y., Huang, W., Niu, L., Umbach, D. M., Covo, S., & Li, L. (2013) · BMC Genomics · doi:10.1186/1471-2164-14-553 · Cited by 75 · see citing works
Diversification of oral and aboral mesodermal regulatory states in pregastrular sea urchin embryos
Materna, S. C., Ransick, A., Li, E., & Davidson, E. H. (2012) · Developmental Biology · doi:10.1016/j.ydbio.2012.11.033 · Cited by 72 · see citing works
Landscapes and archipelagos: spatial organization of gene regulation in vertebrates
Montavon, T., & Duboule, D. (2012) · Trends in Cell Biology · doi:10.1016/j.tcb.2012.04.003 · Cited by 45 · see citing works
Unraveling architecture of the pluripotent genome
Phillips‐Cremins, J. E. (2014) · Current Opinion in Cell Biology · doi:10.1016/j.ceb.2014.04.006 · Cited by 32 · see citing works
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- Authors
- Gómez-Marín, C., Tena, J. J., Acemel, R. D., López-Mayorga, M., Naranjo, S., de la Calle-Mustienes, E., Maeso, I., Beccari, L., Aneas, I., Vielmas, E., Bovolenta, P., Nobrega, M. A., Carvajal, J., & Gómez-Skarmeta, J. L.
- Affiliations
- Consejo Superior de Investigaciones Científicas (ES)
- Centro Andaluz de Biología del Desarrollo, Consejo Superior de Investigaciones Científicas/Universidad Pablo de Olavide, Seville 41013, Spain;
- University of Chicago (US)
- California Institute of Technology (US)
- Department of Human Genetics, University of Chicago, IL 60637;
- ORCID
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2015-06
- Volume
- 112
- Issue
- 24
- Pages
- 7542-7547
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC4475986
- OpenAlex
- W1637500350
- Cited by
- 159
- References
- 40
- Citations by year
- 2026: 6 · 2025: 6 · 2024: 4 · 2023: 9 · 2022: 9 · 2021: 18 · 2020: 15 · 2019: 21 · 2018: 16 · 2017: 21 · 2016: 28 · 2015: 6
- FWCI
- 10.28
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- CaltechAUTHORS (California Institute of Technology) (submittedVersion)
- DIGITAL.CSIC (Spanish National Research Council (CSIC)) (submittedVersion)
- Funders
- Ministry of Economy and Competitiveness | Consejo Superior de Investigaciones Científicas (BFU2013-41322-P, BFU2011-22928, BFU2013-43213-P, BFU2014-55738-REDT)
- Consejería Economía, Innovación, Ciencia y Empleo, Junta de Andalucia (BIO-396)
- EU-FP7-PEOPLE 2011-CIG (303904 EPAXIALMYF5KO)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Life Sciences › Agricultural and Biological Sciences › Plant Science › Chromosomal and Genetic Variations
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Developmental Biology and Gene Regulation
- Keywords
- topologically associating domains, CTCF, 3D genome organization, gene clusters, regulatory landscape, evolutionary conservation, deuterostome evolution, zebrafish, Hi-C, chromatin compartmentalization
- MeSH terms
- CCCTC-Binding Factor, Animals, Base Sequence, Binding Sites, Chromatin, DNA, Enhancer Elements, Genetic, Genes, Homeobox, Multigene Family, Humans, Models, Genetic, Promoter Regions, Genetic, Repressor Proteins, Zebrafish, Conserved Sequence, Homeodomain Proteins, Evolution, Molecular, Animals, Genetically Modified, Strongylocentrotus purpuratus, Mice, Protein Interaction Domains and Motifs
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