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Advances in higher-order chromatin architecture: the move towards 4D genome

  • Jung, Namyoung (Department of Life Sciences, Pohang University of Science and Technology (POSTECH)) ;
  • Kim, Tae-Kyung (Department of Life Sciences, Pohang University of Science and Technology (POSTECH))
  • Received : 2021.02.19
  • Accepted : 2021.04.12
  • Published : 2021.05.31

Abstract

In eukaryotes, the genome is hierarchically packed inside the nucleus, which facilitates physical contact between cis-regulatory elements (CREs), such as enhancers and promoters. Accumulating evidence highlights the critical role of higher-order chromatin structure in precise regulation of spatiotemporal gene expression under diverse biological contexts including lineage commitment and cell activation by external stimulus. Genomics and imaging-based technologies, such as Hi-C and DNA fluorescence in situ hybridization (FISH), have revealed the key principles of genome folding, while newly developed tools focus on improvement in resolution, throughput and modality at single-cell and population levels, and challenge the knowledge obtained through conventional approaches. In this review, we discuss recent advances in our understanding of principles of higher-order chromosome conformation and technologies to investigate 4D chromatin interactions.

Keywords

Acknowledgement

This work was funded by National Research Foundation of Korea (NRF) grants from the Korea government (MSIT) (NRF-2019R1A2C2006740, NRF-2019R1A5A6099645, NRF-2017M3A9G7073033, NRF-2019M3C7A1031537, and NRF-2020H1D3A1A04104610) (T.-K. K.).

References

  1. Van Bortle K and Corces VG (2012) Nuclear organization and genome function. Annu Rev Cell Dev Biol 28, 163-187 https://doi.org/10.1146/annurev-cellbio-101011-155824
  2. Rowley MJ and Corces VG (2018) Organizational principles of 3D genome architecture. Nat Rev Genet 19, 789-800 https://doi.org/10.1038/s41576-018-0060-8
  3. Bonev B and Cavalli G (2016) Organization and function of the 3D genome. Nat Rev Genet 17, 661-678 https://doi.org/10.1038/nrg.2016.112
  4. Zheng H and Xie W (2019) The role of 3D genome organization in development and cell differentiation. Nat Rev Mol Cell Biol 20, 535-550 https://doi.org/10.1038/s41580-019-0132-4
  5. Dekker J, Belmont AS, Guttman M et al (2017) The 4D nucleome project. Nature 549, 219-226 https://doi.org/10.1038/nature23884
  6. Sparks TM, Harabula I and Pombo A (2020) Evolving methodologies and concepts in 4D nucleome research. Curr Opin Cell Biol 64, 105-111 https://doi.org/10.1016/j.ceb.2020.04.005
  7. Kempfer R and Pombo A (2020) Methods for mapping 3D chromosome architecture. Nat Rev Genet 21, 207-226 https://doi.org/10.1038/s41576-019-0195-2
  8. Beagrie RA, Scialdone A, Schueler M et al (2017) Complex multi-enhancer contacts captured by genome architecture mapping. Nature 543, 519-524 https://doi.org/10.1038/nature21411
  9. Beliveau BJ, Joyce EF, Apostolopoulos N et al (2012) Versatile design and synthesis platform for visualizing genomes with Oligopaint FISH probes. Proc Natl Acad Sci U S A 109, 21301-21306 https://doi.org/10.1073/pnas.1213818110
  10. Bintu B, Mateo LJ, Su JH et al (2018) Super-resolution chromatin tracing reveals domains and cooperative interactions in single cells. Science 362, eaau1783 https://doi.org/10.1126/science.aau1783
  11. Hu M and Wang S (2021) Chromatin tracing: imaging 3D genome and nucleome. Trends Cell Biol 31, 5-8 https://doi.org/10.1016/j.tcb.2020.10.006
  12. Wang S, Su JH, Beliveau BJ et al (2016) Spatial organization of chromatin domains and compartments in single chromosomes. Science 353, 598-602 https://doi.org/10.1126/science.aaf8084
  13. Li G, Liu Y, Zhang Y et al (2019) Joint profiling of DNA methylation and chromatin architecture in single cells. Nat Methods 16, 991-993
  14. Lee DS, Luo C, Zhou J et al (2019) Simultaneous profiling of 3D genome structure and DNA methylation in single human cells. Nat Methods 16, 999-1006 https://doi.org/10.1038/s41592-019-0547-z
  15. Su JH, Zheng P, Kinrot SS, Bintu B and Zhuang X (2020) Genome-scale imaging of the 3D organization and transcriptional activity of chromatin. Cell 182, 1641-1659 e26 https://doi.org/10.1016/j.cell.2020.07.032
  16. Nagano T, Lubling Y, Stevens TJ et al (2013) Single-cell Hi-C reveals cell-to-cell variability in chromosome structure. Nature 502, 59-64 https://doi.org/10.1038/nature12593
  17. Nagano T, Lubling Y, Varnai C et al (2017) Cell-cycle dynamics of chromosomal organization at single-cell resolution. Nature 547, 61-67 https://doi.org/10.1038/nature23001
  18. Gorkin DU, Leung D and Ren B (2014) The 3D genome in transcriptional regulation and pluripotency. Cell Stem Cell 14, 762-775 https://doi.org/10.1016/j.stem.2014.05.017
  19. Cremer T and Cremer M (2010) Chromosome territories. Cold Spring Harb Perspect Biol 2, a003889 https://doi.org/10.1101/cshperspect.a003889
  20. Lieberman-Aiden E, van Berkum NL, Williams L et al (2009) Comprehensive mapping of long-range interactions reveals folding principles of the human genome. Science 326, 289-293 https://doi.org/10.1126/science.1181369
  21. Solovei I, Wang AS, Thanisch K et al (2013) LBR and lamin A/C sequentially tether peripheral heterochromatin and inversely regulate differentiation. Cell 152, 584-598 https://doi.org/10.1016/j.cell.2013.01.009
  22. Hildebrand EM and Dekker J (2020) Mechanisms and functions of chromosome compartmentalization. Trends Biochem Sci 45, 385-396 https://doi.org/10.1016/j.tibs.2020.01.002
  23. Hu S, Lv P, Yan Z and Wen B (2019) Disruption of nuclear speckles reduces chromatin interactions in active compartments. Epigenetics Chromatin 12, 43 https://doi.org/10.1186/s13072-019-0289-2
  24. Alberti S, Gladfelter A and Mittag T (2019) Considerations and challenges in studying liquid-liquid phase separation and biomolecular condensates. Cell 176, 419-434 https://doi.org/10.1016/j.cell.2018.12.035
  25. Strom AR, Emelyanov AV, Mir M, Fyodorov DV, Darzacq X and Karpen GH (2017) Phase separation drives heterochromatin domain formation. Nature 547, 241-245 https://doi.org/10.1038/nature22989
  26. Larson AG, Elnatan D, Keenen MM et al (2017) Liquid droplet formation by HP1alpha suggests a role for phase separation in heterochromatin. Nature 547, 236-240 https://doi.org/10.1038/nature22822
  27. Sanulli S, Trnka MJ, Dharmarajan V et al (2019) HP1 reshapes nucleosome core to promote phase separation of heterochromatin. Nature 575, 390-394 https://doi.org/10.1038/s41586-019-1669-2
  28. Wang L, Gao Y, Zheng X et al (2019) Histone modifications regulate chromatin compartmentalization by contributing to a phase separation mechanism. Mol Cell 76, 646-659 e6 https://doi.org/10.1016/j.molcel.2019.08.019
  29. Plys AJ, Davis CP, Kim J et al (2019) Phase separation of Polycomb-repressive complex 1 is governed by a charged disordered region of CBX2. Genes Dev 33, 799-813 https://doi.org/10.1101/gad.326488.119
  30. Gibson BA, Doolittle LK, Schneider MWG et al (2019) Organization of chromatin by intrinsic and regulated phase separation. Cell 179, 470-484 e21 https://doi.org/10.1016/j.cell.2019.08.037
  31. Laflamme G and Mekhail K (2020) Biomolecular condensates as arbiters of biochemical reactions inside the nucleus. Commun Biol 3, 773 https://doi.org/10.1038/s42003-020-01517-9
  32. Dixon JR, Selvaraj S, Yue F et al (2012) Topological domains in mammalian genomes identified by analysis of chromatin interactions. Nature 485, 376-380 https://doi.org/10.1038/nature11082
  33. Nora EP, Lajoie BR, Schulz EG et al (2012) Spatial partitioning of the regulatory landscape of the X-inactivation centre. Nature 485, 381-385 https://doi.org/10.1038/nature11049
  34. Sexton T, Yaffe E, Kenigsberg E et al (2012) Threedimensional folding and functional organization principles of the Drosophila genome. Cell 148, 458-472 https://doi.org/10.1016/j.cell.2012.01.010
  35. Zuin J, Dixon JR, van der Reijden MI et al (2014) Cohesin and CTCF differentially affect chromatin architecture and gene expression in human cells. Proc Natl Acad Sci U S A 111, 996-1001 https://doi.org/10.1073/pnas.1317788111
  36. Rao SS, Huntley MH, Durand NC et al (2014) A 3D map of the human genome at kilobase resolution reveals principles of chromatin looping. Cell 159, 1665-1680 https://doi.org/10.1016/j.cell.2014.11.021
  37. Eres IE and Gilad Y (2020) A TAD Skeptic: Is 3D genome topology conserved? Trends Genet 37, 216-223 https://doi.org/10.1016/j.tig.2020.10.009
  38. Eres IE, Luo K, Hsiao CJ, Blake LE and Gilad Y (2019) Reorganization of 3D genome structure may contribute to gene regulatory evolution in primates. PLoS Genet 15, e1008278 https://doi.org/10.1371/journal.pgen.1008278
  39. Dong P, Tu X, Chu PY et al (2017) 3D chromatin architecture of large plant genomes determined by local a/b compartments. Mol Plant 10, 1497-1509 https://doi.org/10.1016/j.molp.2017.11.005
  40. Xie T, Zhang FG, Zhang HY, Wang XT, Hu JH and Wu XM (2019) Biased gene retention during diploidization in Brassica linked to three-dimensional genome organization. Nat Plants 5, 822-832 https://doi.org/10.1038/s41477-019-0479-8
  41. Finn EH, Pegoraro G, Brandao HB et al (2019) Extensive heterogeneity and intrinsic variation in spatial genome organization. Cell 176, 1502-1515 e10 https://doi.org/10.1016/j.cell.2019.01.020
  42. Flyamer IM, Gassler J, Imakaev M et al (2017) Single-nucleus Hi-C reveals unique chromatin reorganization at oocyte-to-zygote transition. Nature 544, 110-114 https://doi.org/10.1038/nature21711
  43. Tan L, Xing D, Chang CH, Li H and Xie XS (2018) Three-dimensional genome structures of single diploid human cells. Science 361, 924-928 https://doi.org/10.1126/science.aat5641
  44. Pombo A and Dillon N (2015) Three-dimensional genome architecture: players and mechanisms. Nat Rev Mol Cell Biol 16, 245-257 https://doi.org/10.1038/nrm3965
  45. Javierre BM, Burren OS, Wilder SP et al (2016) Lineage-specific genome architecture links enhancers and non-coding disease variants to target gene promoters. Cell 167, 1369-1384 e19 https://doi.org/10.1016/j.cell.2016.09.037
  46. Schoenfelder S and Fraser P (2019) Long-range enhancer-promoter contacts in gene expression control. Nat Rev Genet 20, 437-455 https://doi.org/10.1038/s41576-019-0128-0
  47. Yokoshi M, Segawa K and Fukaya T (2020) Visualizing the role of boundary elements in enhancer-promoter communication. Mol Cell 78, 224-235 e5 https://doi.org/10.1016/j.molcel.2020.02.007
  48. Galupa R and Crocker J (2020) Enhancer-promoter communication: thinking outside the TAD. Trends Genet 36, 459-461 https://doi.org/10.1016/j.tig.2020.04.002
  49. Beagan JA and Phillips-Cremins JE (2020) On the existence and functionality of topologically associating domains. Nat Genet 52, 8-16 https://doi.org/10.1038/s41588-019-0561-1
  50. Terakawa T, Bisht S, Eeftens JM, Dekker C, Haering CH and Greene EC (2017) The condensin complex is a mechanochemical motor that translocates along DNA. Science 358, 672-676 https://doi.org/10.1126/science.aan6516
  51. Ganji M, Shaltiel IA, Bisht S et al (2018) Real-time imaging of DNA loop extrusion by condensin. Science 360, 102-105 https://doi.org/10.1126/science.aar7831
  52. Stigler J, Camdere GO, Koshland DE and Greene EC (2016) Single-molecule imaging reveals a collapsed conformational state for DNA-bound cohesin. Cell Rep 15, 988-998 https://doi.org/10.1016/j.celrep.2016.04.003
  53. Davidson IF, Goetz D, Zaczek MP et al (2016) Rapid movement and transcriptional re-localization of human cohesin on DNA. EMBO J 35, 2671-2685 https://doi.org/10.15252/embj.201695402
  54. Kanke M, Tahara E, Huis In't Veld PJ and Nishiyama T (2016) Cohesin acetylation and Wapl-Pds5 oppositely regulate translocation of cohesin along DNA. EMBO J 35, 2686-2698 https://doi.org/10.15252/embj.201695756
  55. Dixon JR, Gorkin DU and Ren B (2016) Chromatin domains: the unit of chromosome organization. Mol Cell 62, 668-680 https://doi.org/10.1016/j.molcel.2016.05.018
  56. Deng W, Rupon JW, Krivega I et al (2014) Reactivation of developmentally silenced globin genes by forced chromatin looping. Cell 158, 849-860 https://doi.org/10.1016/j.cell.2014.05.050
  57. Palstra RJ, Tolhuis B, Splinter E, Nijmeijer R, Grosveld F and de Laat W (2003) The beta-globin nuclear compartment in development and erythroid differentiation. Nat Genet 35, 190-194 https://doi.org/10.1038/ng1244
  58. Robson MI, Ringel AR and Mundlos S (2019) Regulatory landscaping: how enhancer-promoter communication is sculpted in 3D. Mol Cell 74, 1110-1122 https://doi.org/10.1016/j.molcel.2019.05.032
  59. Mifsud B, Tavares-Cadete F, Young AN et al (2015) Mapping long-range promoter contacts in human cells with high-resolution capture Hi-C. Nat Genet 47, 598- 606 https://doi.org/10.1038/ng.3286
  60. Pattison JM, Melo SP, Piekos SN et al (2018) Retinoic acid and BMP4 cooperate with p63 to alter chromatin dynamics during surface epithelial commitment. Nat Genet 50, 1658-1665 https://doi.org/10.1038/s41588-018-0263-0
  61. Mumbach MR, Satpathy AT, Boyle EA et al (2017) Enhancer connectome in primary human cells identifies target genes of disease-associated DNA elements. Nat Genet 49, 1602-1612 https://doi.org/10.1038/ng.3963
  62. Mumbach MR, Rubin AJ, Flynn RA et al (2016) HiChIP: efficient and sensitive analysis of protein-directed genome architecture. Nat Methods 13, 919-922 https://doi.org/10.1038/nmeth.3999
  63. Rubin AJ, Barajas BC, Furlan-Magaril M et al (2017) Lineage-specific dynamic and pre-established enhancer-promoter contacts cooperate in terminal differentiation. Nat Genet 49, 1522-1528 https://doi.org/10.1038/ng.3935
  64. Kagey MH, Newman JJ, Bilodeau S et al (2010) Mediator and cohesin connect gene expression and chromatin architecture. Nature 467, 430-435 https://doi.org/10.1038/nature09380
  65. Kim S and Shendure J (2019) Mechanisms of interplay between transcription factors and the 3D genome. Mol Cell 76, 306-319 https://doi.org/10.1016/j.molcel.2019.08.010
  66. Weintraub AS, Li CH, Zamudio AV et al (2017) YY1 Is a structural regulator of enhancer-promoter loops. Cell 171, 1573-1588 e28 https://doi.org/10.1016/j.cell.2017.11.008
  67. Thakur J and Henikoff S (2020) Architectural RNA in chromatin organization. Biochem Soc Trans 48, 1967-1978 https://doi.org/10.1042/BST20191226
  68. Isoda T, Moore AJ, He Z et al (2017) Non-coding transcription instructs chromatin folding and compartmentalization to dictate enhancer-promoter communication and T cell fate. Cell 171, 103-119 e18 https://doi.org/10.1016/j.cell.2017.09.001
  69. Dekker J, Rippe K, Dekker M and Kleckner N (2002) Capturing chromosome conformation. Science 295, 1306-1311 https://doi.org/10.1126/science.1067799
  70. van de Werken HJ, Landan G, Holwerda SJ et al (2012) Robust 4C-seq data analysis to screen for regulatory DNA interactions. Nat Methods 9, 969-972 https://doi.org/10.1038/nmeth.2173
  71. Dostie J, Richmond TA, Arnaout RA et all (2006) Chromosome conformation capture carbon copy (5C): a massively parallel solution for mapping interactions between genomic elements. Genome Res 16, 1299-1309 https://doi.org/10.1101/gr.5571506
  72. Hsieh TH, Weiner A, Lajoie B, Dekker J, Friedman N and Rando OJ (2015) Mapping nucleosome resolution chromosome folding in yeast by Micro-C. Cell 162, 108-119 https://doi.org/10.1016/j.cell.2015.05.048
  73. Hsieh TS, Cattoglio C, Slobodyanyuk E et al (2020) Resolving the 3D landscape of transcription-linked mammalian chromatin folding. Mol Cell 78, 539-553 e8 https://doi.org/10.1016/j.molcel.2020.03.002
  74. Ma W, Ay F, Lee C et al (2015) Fine-scale chromatin interaction maps reveal the cis-regulatory landscape of human lincRNA genes. Nat Methods 12, 71-78 https://doi.org/10.1038/nmeth.3205
  75. Ramani V, Cusanovich DA, Hause RJ et al (2016) Mapping 3D genome architecture through in situ DNase Hi-C. Nat Protoc 11, 2104-2121 https://doi.org/10.1038/nprot.2016.126
  76. Fullwood MJ, Liu MH, Pan YF et al (2009) An oestrogen-receptor-alpha-bound human chromatin interactome. Nature 462, 58-64 https://doi.org/10.1038/nature08497
  77. Li X, Luo OJ, Wang P et al (2017) Long-read ChIA-PET for base-pair-resolution mapping of haplotype-specific chromatin interactions. Nat Protoc 12, 899-915 https://doi.org/10.1038/nprot.2017.012
  78. Fang R, Yu M, Li G et al (2016) Mapping of long-range chromatin interactions by proximity ligation-assisted ChIP-seq. Cell Res 26, 1345-1348 https://doi.org/10.1038/cr.2016.137
  79. Hughes JR, Roberts N, McGowan S et al (2014) Analysis of hundreds of cis-regulatory landscapes at high resolution in a single, high-throughput experiment. Nat Genet 46, 205-212 https://doi.org/10.1038/ng.2871
  80. Mumbach MR, Granja JM, Flynn RA et al (2019) HiChIRP reveals RNA-associated chromosome conformation. Nat Methods 16, 489-492 https://doi.org/10.1038/s41592-019-0407-x
  81. Ramani V, Deng X, Qiu R et al (2017) Massively multiplex single-cell Hi-C. Nat Methods 14, 263-266 https://doi.org/10.1038/nmeth.4155
  82. Cusanovich DA, Daza R, Adey A et al (2015) Multiplex single cell profiling of chromatin accessibility by combinatorial cellular indexing. Science 348, 910-914 https://doi.org/10.1126/science.aab1601
  83. Klein AM, Mazutis L, Akartuna I et al (2015) Droplet barcoding for single-cell transcriptomics applied to embryonic stem cells. Cell 161, 1187-1201 https://doi.org/10.1016/j.cell.2015.04.044
  84. Macosko EZ, Basu A, Satija R et al (2015) Highly parallel genome-wide expression profiling of individual cells using nanoliter droplets. Cell 161, 1202-1214 https://doi.org/10.1016/j.cell.2015.05.002
  85. Rotem A, Ram O, Shoresh N et al (2015) Single-cell ChIP-seq reveals cell subpopulations defined by chromatin state. Nat Biotechnol 33, 1165-1172 https://doi.org/10.1038/nbt.3383
  86. Ramani V, Deng X, Qiu R et al (2020) Sci-Hi-C: A single-cell Hi-C method for mapping 3D genome organization in large number of single cells. Methods 170, 61-68 https://doi.org/10.1016/j.ymeth.2019.09.012
  87. Quinodoz SA, Ollikainen N, Tabak B et al (2018) Higher-order inter-chromosomal hubs shape 3D genome organization in the nucleus. Cell 174, 744-757 e24 https://doi.org/10.1016/j.cell.2018.05.024
  88. Zheng M, Tian SZ, Capurso D et al (2019) Multiplex chromatin interactions with single-molecule precision. Nature 566, 558-562 https://doi.org/10.1038/s41586-019-0949-1
  89. Wang G, Achim CL, Hamilton RL, Wiley CA and Soontornniyomkij V (1999) Tyramide signal amplification method in multiple-label immunofluorescence confocal microscopy. Methods 18, 459-464 https://doi.org/10.1006/meth.1999.0813
  90. Chen Y, Zhang Y, Wang Y et al (2018) Mapping 3D genome organization relative to nuclear compartments using TSA-Seq as a cytological ruler. J Cell Biol 217, 4025-4048 https://doi.org/10.1083/jcb.201807108
  91. Zhang L, Zhang Y, Chen Y et al (2020) TSA-seq reveals a largely conserved genome organization relative to nuclear speckles with small position changes tightly correlated with gene expression changes. Genome Res 31, 251-264 https://doi.org/10.1101/gr.266239.120
  92. Speicher MR, Gwyn Ballard S and Ward DC (1996) Karyotyping human chromosomes by combinatorial multi-fluor FISH. Nat Genet 12, 368-375 https://doi.org/10.1038/ng0496-368
  93. Agbleke AA, Amitai A, Buenrostro JD et al (2020) Advances in chromatin and chromosome research: perspectives from multiple fields. Mol Cell 79, 881-901 https://doi.org/10.1016/j.molcel.2020.07.003
  94. Gnirke A, Melnikov A, Maguire J et al (2009) Solution hybrid selection with ultra-long oligonucleotides for massively parallel targeted sequencing. Nat Biotechnol 27, 182-189 https://doi.org/10.1038/nbt.1523
  95. Beliveau BJ, Boettiger AN, Avendano MS et al (2015) Single-molecule super-resolution imaging of chromosomes and in situ haplotype visualization using Oligopaint FISH probes. Nat Commun 6, 7147 https://doi.org/10.1038/ncomms8147
  96. Mateo LJ, Murphy SE, Hafner A, Cinquini IS, Walker CA and Boettiger AN (2019) Visualizing DNA folding and RNA in embryos at single-cell resolution. Nature 568, 49-54 https://doi.org/10.1038/s41586-019-1035-4
  97. Sawh AN, Shafer MER, Su JH, Zhuang X, Wang S and Mango SE (2020) Lamina-dependent stretching and unconventional chromosome compartments in early C. elegans embryos. Mol Cell 78, 96-111 e6 https://doi.org/10.1016/j.molcel.2020.02.006
  98. Liu M, Lu Y, Yang B et al (2020) Multiplexed imaging of nucleome architectures in single cells of mammalian tissue. Nat Commun 11, 2907 https://doi.org/10.1038/s41467-020-16732-5
  99. Lakadamyali M and Cosma MP (2020) Visualizing the genome in high resolution challenges our textbook understanding. Nat Methods 17, 371-379 https://doi.org/10.1038/s41592-020-0758-3
  100. Chen B, Gilbert LA, Cimini BA et al (2013) Dynamic imaging of genomic loci in living human cells by an optimized CRISPR/Cas system. Cell 155, 1479-1491 https://doi.org/10.1016/j.cell.2013.12.001
  101. Ma H, Naseri A, Reyes-Gutierrez P, Wolfe SA, Zhang S and Pederson T (2015) Multicolor CRISPR labeling of chromosomal loci in human cells. Proc Natl Acad Sci U S A 112, 3002-3007 https://doi.org/10.1073/pnas.1420024112
  102. Shao S, Zhang W, Hu H et al (2016) Long-term dual-color tracking of genomic loci by modified sgRNAs of the CRISPR/Cas9 system. Nucleic Acids Res 44, e86 https://doi.org/10.1093/nar/gkw066
  103. Wang S, Su JH, Zhang F and Zhuang X (2016) An RNA-aptamer-based two-color CRISPR labeling system. Sci Rep 6, 26857 https://doi.org/10.1038/srep26857
  104. Fu Y, Rocha PP, Luo VM et al (2016) CRISPR-dCas9 and sgRNA scaffolds enable dual-colour live imaging of satellite sequences and repeat-enriched individual loci. Nat Commun 7, 11707 https://doi.org/10.1038/ncomms11707
  105. Ma H, Tu LC, Naseri A et al (2016) Multiplexed labeling of genomic loci with dCas9 and engineered sgRNAs using CRISPRainbow. Nat Biotechnol 34, 528-530 https://doi.org/10.1038/nbt.3526
  106. Chen B, Zou W, Xu H, Liang Y and Huang B (2018) Efficient labeling and imaging of protein-coding genes in living cells using CRISPR-Tag. Nat Commun 9, 5065 https://doi.org/10.1038/s41467-018-07498-y
  107. Gu B, Swigut T, Spencley A et al (2018) Transcription-coupled changes in nuclear mobility of mammalian cis-regulatory elements. Science 359, 1050-1055 https://doi.org/10.1126/science.aao3136