Abstract
The spatial structure of the orderly organized chromatin in the nucleus has important roles in maintaining normal cell function and in regulation of gene expression, and the high-throughput Hi-C and ChIA-PET methods have been widely used in various biological studies for determining potential spatial genome structures and their functions. However, there are still great difficulties and challenges in three-dimensional (3D) genomics research. More efficient, economical, and unbiased approaches to studying 3D genomics need to be developed for more widespread and easier applications. Here, we review the most recent studies on new 3D genomics research technologies, such as improvements of the traditional Hi-C and ChIA-PET methods, new approaches based on non-proximal-ligation strategies, and imaging-based methods improved in recent years. Especially, we review the CRISPR-based methods for functional validations in 3D genomics, which could be the forthcoming directions. We hope this review can show some insights into the potential improvements for future 3D genomics.
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References
Abbas, A., He, X., Niu, J., Zhou, B., Zhu, G., Ma, T., Song, J., Gao, J., Zhang, M.Q., and Zeng, J. (2019). Integrating Hi-C and FISH data for modeling of the 3D organization of chromosomes. Nat Commun 10, 2049.
Barutcu, A.R., Lajoie, B.R., McCord, R.P., Tye, C.E., Hong, D., Messier, T. L., Browne, G., van Wijnen, A.J., Lian, J.B., Stein, J.L., et al. (2015). Chromatin interaction analysis reveals changes in small chromosome and telomere clustering between epithelial and breast cancer cells. Genome Biol 16, 214.
Beagrie, R.A., Scialdone, A., Schueler, M., Kraemer, D.C.A., Chotalia, M., Xie, S.Q., Barbieri, M., de Santiago, I., Lavitas, L.M., Branco, M.R., et al. (2017). Complex multi-enhancer contacts captured by genome architecture mapping. Nature 543, 519–524.
Bintu, B., Mateo, L.J., Su, J.H., Sinnott-Armstrong, N.A., Parker, M., Kinrot, S., Yamaya, K., Boettiger, A.N., and Zhuang, X. (2018). Superresolution chromatin tracing reveals domains and cooperative interactions in single cells. Science 362, eaau1783.
Bonev, B., and Cavalli, G. (2016). Erratum: Organization and function of the 3D genome. Nat Rev Genet 17, 772.
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). Multiscale 3D genome rewiring during mouse neural development. Cell 171, 557–572.e24.
Choy, J., and Fullwood, M.J. (2017). Deciphering noncoding RNA and chromatin interactions: multiplex chromatin interaction analysis by paired-end tag sequencing (mChIA-PET). In Enhancer RNAs. (New York, NY: Humana Press), pp. 63–89.
Cremer, M., Schmid, V.J., Kraus, F., Markaki, Y., Hellmann, I., Maiser, A., Leonhardt, H., John, S., Stamatoyannopoulos, J., and Cremer, T. (2017). Initial high-resolution microscopic mapping of active and inactive regulatory sequences proves non-random 3D arrangements in chromatin domain clusters. Epigenet Chromatin 10, 39.
Darrow, E.M., Huntley, M.H., Dudchenko, O., Stamenova, E.K., Durand, N.C., Sun, Z., Huang, S.C., Sanborn, A.L., Machol, I., Shamim, M., et al. (2016). Deletion of DXZ4 on the human inactive X chromosome alters higher-order genome architecture. Proc Natl Acad Sci USA 113, E4504–E4512.
Dekker, J., Belmont, A.S., Guttman, M., Leshyk, V.O., Lis, J.T., Lomvardas, S., Mirny, L.A., O’Shea, C.C., Park, P.J., Ren, B., et al. (2017). The 4D nucleome project. Nature 549, 219–226.
Dekker, J., Rippe, K., Dekker, M., and Kleckner, N. (2002). Capturing chromosome conformation. Science 295, 1306–1311.
Dixon, J.R., Selvaraj, S., Yue, F., Kim, A., Li, Y., Shen, Y., Hu, M., Liu, J. S., and Ren, B. (2012). Topological domains in mammalian genomes identified by analysis of chromatin interactions. Nature 485, 376–380.
Dong, P., Tu, X., Li, H., Zhang, J., Grierson, D., Li, P., and Zhong, S. (2020). Tissue-specific Hi-C analyses of rice, foxtail millet and maize suggest non-canonical function of plant chromatin domains. J Integr Plant Biol 62, 201–217.
Du, Z., Zheng, H., Huang, B., Ma, R., Wu, J., Zhang, X., He, J., Xiang, Y., Wang, Q., Li, Y., et al. (2017). Allelic reprogramming of 3D chromatin architecture during early mammalian development. Nature 547, 232–235.
Dudchenko, O., Batra, S.S., Omer, A.D., Nyquist, S.K., Hoeger, M., Durand, N.C., Shamim, M.S., Machol, I., Lander, E.S., Aiden, A.P., et al. (2017). De novo assembly of the Aedes aegypti genome using Hi-C yields chromosome-length scaffolds. Science 356, 92–95.
Fang, R., Yu, M., Li, G., Chee, S., Liu, T., Schmitt, A.D., and Ren, B. (2016). Mapping of long-range chromatin interactions by proximity ligation-assisted ChIP-seq. Cell Res 26, 1345–1348.
Finn, E.H., Pegoraro, G., Brandão, H.B., Valton, A.L., Oomen, M.E., Dekker, J., Mirny, L., and Misteli, T. (2019). Extensive heterogeneity and intrinsic variation in spatial genome organization. Cell 176, 1502–1515.e10.
Flavahan, W.A., Drier, Y., Liau, B.B., Gillespie, S.M., Venteicher, A.S., Stemmer-Rachamimov, A.O., Suvà, M.L., and Bernstein, B.E. (2016). Insulator dysfunction and oncogene activation in IDH mutant gliomas. Nature 529, 110–114.
Flyamer, I.M., Gassler, J., Imakaev, M., Brandão, H.B., Ulianov, S.V., Abdennur, N., Razin, S.V., Mirny, L.A., and Tachibana-Konwalski, K. (2017). Single-nucleus Hi-C reveals unique chromatin reorganization at oocyte-to-zygote transition. Nature 544, 110–114.
Fullwood, M.J., Liu, M.H., Pan, Y.F., Liu, J., Xu, H., Mohamed, Y.B., Orlov, Y.L., Velkov, S., Ho, A., Mei, P.H., et al. (2009). An oestrogen-receptor-α-bound human chromatin interactome. Nature 462, 58–64.
Guo, Y., Xu, Q., Canzio, D., Shou, J., Li, J., Gorkin, D.U., Jung, I., Wu, H., Zhai, Y., Tang, Y., et al. (2015). CRISPR inversion of CTCF sites alters genome topology and enhancer/promoter function. Cell 162, 900–910.
Han, J., Zhang, Z., and Wang, K. (2018). 3C and 3C-based techniques: the powerful tools for spatial genome organization deciphering. Mol Cytogenet 11, 21.
Hnisz, D., Weintraub, A.S., Day, D.S., Valton, A.L., Bak, R.O., Li, C.H., Goldmann, J., Lajoie, B.R., Fan, Z.P., Sigova, A.A., et al. (2016). Activation of proto-oncogenes by disruption of chromosome neighborhoods. Science 351, 1454–1458.
Hsieh, T.H.S., Weiner, A., Lajoie, B., Dekker, J., Friedman, N., and Rando, O.J. (2015). Mapping nucleosome resolution chromosome folding in yeast by micro-C. Cell 162, 108–119.
Hug, C.B., and Vaquerizas, J.M. (2018). The birth of the 3D genome during early embryonic development. Trends Genet 34, 903–914.
Ke, Y., Xu, Y., Chen, X., Feng, S., Liu, Z., Sun, Y., Yao, X., Li, F., Zhu, W., Gao, L., et al. (2017). 3D chromatin structures of mature gametes and structural reprogramming during mammalian embryogenesis. Cell 170, 367–381.e20.
Koch, L. (2017). A 3D view of genome rearrangements. Nat Rev Genet 18, 456.
Lai, B., Tang, Q., Jin, W., Hu, G., Wangsa, D., Cui, K., Stanton, B.Z., Ren, G., Ding, Y., Zhao, M., et al. (2018). Trac-looping measures genome structure and chromatin accessibility. Nat Methods 15, 741–747.
Lee, D.S., Luo, C., Zhou, J., Chandran, S., Rivkin, A., Bartlett, A., Nery, J. R., Fitzpatrick, C., O’Connor, C., Dixon, J.R., et al. (2019). Simultaneous profiling of 3D genome structure and DNA methylation in single human cells. Nat Methods 16, 999–1006.
Li, A., Yin, X., Xu, B., Wang, D., Han, J., Wei, Y., Deng, Y., Xiong, Y., and Zhang, Z. (2018a). Decoding topologically associating domains with ultra-low resolution Hi-C data by graph structural entropy. Nat Commun 9, 3265.
Li, E., Liu, H., Huang, L., Zhang, X., Dong, X., Song, W., Zhao, H., and Lai, J. (2019a). Long-range interactions between proximal and distal regulatory regions in maize. Nat Commun 10, 2633.
Li, G., Liu, Y., Zhang, Y., Kubo, N., Yu, M., Fang, R., Kellis, M., and Ren, B. (2019b). Joint profiling of DNA methylation and chromatin architecture in single cells. Nat Methods 16, 991–993.
Li, G., Ruan, X., Auerbach, R.K., Sandhu, K.S., Zheng, M., Wang, P., Poh, H.M., Goh, Y., Lim, J., Zhang, J., et al. (2012). Extensive promoter-centered chromatin interactions provide a topological basis for transcription regulation. Cell 148, 84–98.
Li, T., Jia, L., Cao, Y., Chen, Q., and Li, C. (2018b). OCEAN-C: mapping hubs of open chromatin interactions across the genome reveals gene regulatory networks. Genome Biol 19, 54.
Liang, Z., Li, G., Wang, Z., Djekidel, M.N., Li, Y., Qian, M.P., Zhang, M. Q., and Chen, Y. (2017). BL-Hi-C is an efficient and sensitive approach for capturing structural and regulatory chromatin interactions. Nat Commun 8, 1622.
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). Comprehensive mapping of long-range interactions reveals folding principles of the human genome. Science 326, 289–293.
Lin, D., Hong, P., Zhang, S., Xu, W., Jamal, M., Yan, K., Lei, Y., Li, L., Ruan, Y., Fu, Z.F., et al. (2018). Digestion-ligation-only Hi-C is an efficient and cost-effective method for chromosome conformation capture. Nat Genet 50, 754–763.
Liu, X., Zhang, Y., Chen, Y., Li, M., Zhou, F., Li, K., Cao, H., Ni, M., Liu, Y., Gu, Z., et al. (2017). In situ capture of chromatin interactions by biotinylated dCas9. Cell 170, 1028–1043.e19.
Lupiáñez, D.G., Kraft, K., Heinrich, V., Krawitz, P., Brancati, F., Klopocki, E., Horn, D., Kayserili, H., Opitz, J.M., Laxova, R., et al. (2015). Disruptions of topological chromatin domains cause pathogenic rewiring of gene-enhancer interactions. Cell 161, 1012–1025.
Ma, H., Tu, L.C., Naseri, A., Chung, Y.C., Grunwald, D., Zhang, S., and Pederson, T. (2018). CRISPR-Sirius: RNA scaffolds for signal amplification in genome imaging. Nat Methods 15, 928–931.
Ma, H., Tu, L.C., Naseri, A., Huisman, M., Zhang, S., Grunwald, D., and Pederson, T. (2016). Multiplexed labeling of genomic loci with dCas9 and engineered sgRNAs using CRISPRainbow. Nat Biotechnol 34, 528–530.
Mateo, L.J., Murphy, S.E., Hafner, A., Cinquini, I.S., Walker, C.A., and Boettiger, A.N. (2019). Visualizing DNA folding and RNA in embryos at single-cell resolution. Nature 568, 49–54.
Mifsud, B., Tavares-Cadete, F., Young, A.N., Sugar, R., Schoenfelder, S., Ferreira, L., Wingett, S.W., Andrews, S., Grey, W., Ewels, P.A., et al. (2015). Mapping long-range promoter contacts in human cells with high-resolution capture Hi-C. Nat Genet 47, 598–606.
Moon, S.B., Kim, D.Y., Ko, J.H., and Kim, Y.S. (2019). Recent advances in the CRISPR genome editing tool set. Exp Mol Med 51, 1–11.
Morgan, S.L., Mariano, N.C., Bermudez, A., Arruda, N.L., Wu, F., Luo, Y., Shankar, G., Jia, L., Chen, H., Hu, J.F., et al. (2017). Manipulation of nuclear architecture through CRISPR-mediated chromosomal looping. Nat Commun 8, 15993.
Mumbach, M.R., Rubin, A.J., Flynn, R.A., Dai, C., Khavari, P.A., Greenleaf, W.J., and Chang, H.Y. (2016). HiChIP: efficient and sensitive analysis of protein-directed genome architecture. Nat Methods 13, 919–922.
Nagano, T., Lubling, Y., Stevens, T.J., Schoenfelder, S., Yaffe, E., Dean, W., Laue, E.D., Tanay, A., and Fraser, P. (2013). Single-cell Hi-C reveals cell-to-cell variability in chromosome structure. Nature 502, 59–64.
Ni, Y., Cao, B., Ma, T., Niu, G., Huo, Y., Huang, J., Chen, D., Liu, Y., Yu, B., Zhang, M.Q., et al. (2017). Super-resolution imaging of a 2.5 kb non-repetitive DNA in situ in the nuclear genome using molecular beacon probes. eLife 6, e21660.
Niu, L., Shen, W., Huang, Y., He, N., Zhang, Y., Sun, J., Wan, J., Jiang, D., Yang, M., Tse, Y.C., et al. (2019). Amplification-free library preparation with SAFE Hi-C uses ligation products for deep sequencing to improve traditional Hi-C analysis. Commun Biol 2, 267.
Ohno, M., Ando, T., Priest, D.G., Kumar, V., Yoshida, Y., and Taniguchi, Y. (2019). Sub-nucleosomal genome structure reveals distinct nucleosome folding motifs. Cell 176, 520–534.e25.
Olivares-Chauvet, P., Mukamel, Z., Lifshitz, A., Schwartzman, O., Elkayam, N.O., Lubling, Y., Deikus, G., Sebra, R.P., and Tanay, A. (2016). Capturing pairwise and multi-way chromosomal conformations using chromosomal walks. Nature 540, 296–300.
Oluwadare, O., and Cheng, J. (2017). ClusterTAD: an unsupervised machine learning approach to detecting topologically associated domains of chromosomes from Hi-C data. BMC Bioinformatics 18, 480.
Orlando, G., Law, P.J., Cornish, A.J., Dobbins, S.E., Chubb, D., Broderick, P., Litchfield, K., Hariri, F., Pastinen, T., Osborne, C.S., et al. (2018). Promoter capture Hi-C-based identification of recurrent noncoding mutations in colorectal cancer. Nat Genet 50, 1375–1380.
Ou, H.D., Phan, S., Deerinck, T.J., Thor, A., Ellisman, M.H., and O’Shea, C.C. (2017). ChromEMT: Visualizing 3D chromatin structure and compaction in interphase and mitotic cells. Science 357, eaag0025.
Peng, Y., Xiong, D., Zhao, L., Ouyang, W., Wang, S., Sun, J., Zhang, Q., Guan, P., Xie, L., Li, W., et al. (2019). Chromatin interaction maps reveal genetic regulation for quantitative traits in maize. Nat Commun 10, 2632.
Quinodoz, S.A., Ollikainen, N., Tabak, B., Palla, A., Schmidt, J.M., Detmar, E., Lai, M.M., Shishkin, A.A., Bhat, P., Takei, Y., et al. (2018). Higher-order inter-chromosomal hubs shape 3D genome organization in the nucleus. Cell 174, 744–757.e24.
Ramani, V., Deng, X., Qiu, R., Gunderson, K.L., Steemers, F.J., Disteche, C.M., Noble, W.S., Duan, Z., and Shendure, J. (2017). Massively multiplex single-cell Hi-C. Nat Methods 14, 263–266.
Risca, V.I., Denny, S.K., Straight, A.F., and Greenleaf, W.J. (2017). Variable chromatin structure revealed by in situ spatially correlated DNA cleavage mapping. Nature 541, 237–241.
Robinson, D.R., Wu, Y.M., Lonigro, R.J., Vats, P., Cobain, E., Everett, J., Cao, X., Rabban, E., Kumar-Sinha, C., Raymond, V., et al. (2017). Integrative clinical genomics of metastatic cancer. Nature 548, 297–303.
Rowley, M.J., and Corces, V.G. (2018). Organizational principles of 3D genome architecture. Nat Rev Genet 19, 789–800.
Sexton, T., Yaffe, E., Kenigsberg, E., Bantignies, F., Leblanc, B., Hoichman, M., Parrinello, H., Tanay, A., and Cavalli, G. (2012). Three-dimensional folding and functional organization principles of the Drosophila genome. Cell 148, 458–472.
Stevens, T.J., Lando, D., Basu, S., Atkinson, L.P., Cao, Y., Lee, S.F., Leeb, M., Wohlfahrt, K.J., Boucher, W., O’Shaughnessy-Kirwan, A., et al. (2017). 3D structures of individual mammalian genomes studied by single-cell Hi-C. Nature 544, 59–64.
Symmons, O., Pan, L., Remeseiro, S., Aktas, T., Klein, F., Huber, W., and Spitz, F. (2016). The Shh topological domain facilitates the action of remote enhancers by reducing the effects of genomic distances. Dev Cell 39, 529–543.
Tan, L., Xing, D., Chang, C.H., Li, H., and Xie, X.S. (2018). Three-dimensional genome structures of single diploid human cells. Science 361, 924–928.
Tang, Z., Luo, O.J., Li, X., Zheng, M., Zhu, J.J., Szalaj, P., Trzaskoma, P., Magalska, A., Wlodarczyk, J., Ruszczycki, B., et al. (2015). CTCF-mediated human 3D genome architecture reveals chromatin topology for transcription. Cell 163, 1611–1627.
Umlauf, D., and Mourad, R. (2019). The 3D genome: From fundamental principles to disease and cancer. Semin Cell Dev Biol 90, 128–137.
Wang, H., Xu, X., Nguyen, C.M., Liu, Y., Gao, Y., Lin, X., Daley, T., Kipniss, N.H., La Russa, M., and Qi, L.S. (2018). CRISPR-mediated programmable 3D genome positioning and nuclear organization. Cell 175, 1405–1417.e14.
Wang, X.T., Cui, W., and Peng, C. (2017). HiTAD: detecting the structural and functional hierarchies of topologically associating domains from chromatin interactions. Nucleic Acids Res 45, e163.
Yaffe, E., and Tanay, A. (2011). Probabilistic modeling of Hi-C contact maps eliminates systematic biases to characterize global chromosomal architecture. Nat Genet 43, 1059–1065.
Yu, W., He, B., and Tan, K. (2017). Identifying topologically associating domains and subdomains by Gaussian mixture model and proportion test. Nat Commun 8, 535.
Zhang, X., Zhang, S., Zhao, Q., Ming, R., and Tang, H. (2019a). Assembly of allele-aware, chromosomal-scale autopolyploid genomes based on Hi-C data. Nat Plants 5, 833–845.
Zhang, Y., Wong, C.H., Birnbaum, R.Y., Li, G., Favaro, R., Ngan, C.Y., Lim, J., Tai, E., Poh, H.M., Wong, E., et al. (2013). Chromatin connectivity maps reveal dynamic promoter-enhancer long-range associations. Nature 504, 306–310.
Zhang, Z., Chng, K.R., Lingadahalli, S., Chen, Z., Liu, M.H., Do, H.H., Cai, S., Rinaldi, N., Poh, H.M., Li, G., et al. (2019b). An AR-ERG transcriptional signature defined by long-range chromatin interactomes in prostate cancer cells. Genome Res 29, 223–235.
Zhao, L., Wang, S., Cao, Z., Ouyang, W., Zhang, Q., Xie, L., Zheng, R., Guo, M., Ma, M., Hu, Z., et al. (2019). Chromatin loops associated with active genes and heterochromatin shape rice genome architecture for transcriptional regulation. Nat Commun 10, 3640.
Zheng, M., Tian, S.Z., Capurso, D., Kim, M., Maurya, R., Lee, B., Piecuch, E., Gong, L., Zhu, J.J., Li, Z., et al. (2019). Multiplex chromatin interactions with single-molecule precision. Nature 566, 558–562.
Zhu, G., Deng, W., Hu, H., Ma, R., Zhang, S., Yang, J., Peng, J., Kaplan, T., and Zeng, J. (2018). Reconstructing spatial organizations of chromosomes through manifold learning. Nucleic Acids Res 46, e50.
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This work was supported by the National Natural Science Foundation of China (31771402, 31970590, 31701115) and the Fundamental Research Funds for the Central Universities (2662017PY116). The finders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. The authors apologize to the many scientists who made contributions to the field but were not cited due to space limitations.
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Zhang, Y., Li, G. Advances in technologies for 3D genomics research. Sci. China Life Sci. 63, 811–824 (2020). https://doi.org/10.1007/s11427-019-1704-2
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DOI: https://doi.org/10.1007/s11427-019-1704-2