Advertisement

Quantitative Biology

, Volume 4, Issue 4, pp 302–309 | Cite as

Computational inference of physical spatial organization of eukaryotic genomes

  • Bingxiang Xu
  • Zhihua Zhang
Review

Abstract

Background

Chromosomes are packed in the cell’s nucleus, and chromosomal conformation is critical to nearly all intranuclear biological reactions, including gene transcription and DNA replication. Nevertheless, chromosomal conformation is largely a mystery in terms of its formation and the regulatory machinery that accesses it.

Results

Thanks to recent technological developments, we can now probe chromatin interaction in substantial detail, boosting research interest in modeling genome spatial organization. Here, we review the current computational models that simulate chromosome dynamics, and explain the physical and topological properties of chromosomal conformation, as inferred from these newly generated data.

Conclusions

Novel models shall be developed to address questions beyond averaged structure in the near further.

Keywords

3D genome models simulation 

References

  1. 1.
    Dillon, N. (2008) The impact of gene location in the nucleus on transcriptional regulation. Dev. Cell, 15, 182–186CrossRefPubMedGoogle Scholar
  2. 2.
    Miele, A. and Dekker, J. (2008) Long-range chromosomal interactions and gene regulation. Mol. Biosyst., 4, 1046–1057CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Dekker, J., Rippe, K., Dekker, M., Kleckner, N. (2002) Capturing chromosome conformation. Science, 295,1306–1311CrossRefPubMedGoogle Scholar
  4. 4.
    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, 289–293CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Cremer, M., Grasser, F., Lanctôt, C., Müller, S., Neusser, M., Zinner, R., Solovei, I. and Cremer, T. (2008) Multicolor 3D fluorescence in situ hybridization for imaging interphase chromosomes. In The Nucleus, Hancock. R. Ed. 463, 205–239, Germany: SpringerGoogle Scholar
  6. 6.
    Song, F., Chen, P., Sun, D., Wang, M., Dong, L., Liang, D., Xu, R. M., Zhu, P. and Li, G. (2014) Cryo-EM study of the chromatin fiber reveals a double helix twisted by tetranucleosomal units. Science, 344, 376–380CrossRefPubMedGoogle Scholar
  7. 7.
    Zhu, P. and Li, G. (2016) Structural insights of nucleosome and the 30-nm chromatin fiber. Curr. Opin. Struct. Biol., 36, 106–115CrossRefPubMedGoogle Scholar
  8. 8.
    Naumova, N., Imakaev, M., Fudenberg, G., Zhan, Y., Lajoie, B. R., Mirny, L. A. and Dekker, J. (2013) Organization of the mitotic chromosome. Science, 342, 948–953CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    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) CTCFmediated human 3D genome architecture reveals chromatin topology for transcription. Cell, 163, 1611–1627CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Bickmore, W. A. (2013) The spatial organization of the human genome. Annu. Rev. Genomics Hum. Genet., 14, 67–84CrossRefPubMedGoogle Scholar
  11. 11.
    Selvaraj, S., R Dixon, J., Bansal, V. and Ren, B. (2013) Whole-genome haplotype reconstruction using proximity-ligation and shotgun sequencing. Nat. Biotechnol., 31, 1111–1118CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Klenin, K., Merlitz, H. and Langowski, J. (1998) A Brownian dynamics program for the simulation of linear and circular DNA and other wormlike chain polyelectrolytes. Biophys. J., 74, 780–788CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Bednar, J., Furrer, P., Stasiak, A., Dubochet, J., Egelman, E. H. and Bates, A. D. (1994) The twist, writhe and overall shape of supercoiled DNA change during counterion-induced transition from a loosely to a tightly interwound superhelix: possible implications for DNA structure in vivo. J. Mol. Biol., 235, 825–847CrossRefPubMedGoogle Scholar
  14. 14.
    Grnbech-Jensen, N., Mashl, R. J., Bruinsma, R. F. and Gelbart, W. M. (1997) Counterion-induced attraction between rigid polyelectrolytes. Phys. Rev. Lett., 78, 2477–2480CrossRefGoogle Scholar
  15. 15.
    Langowski, J. and Heermann, D.W. (2007) Computational modeling of the chromatin fiber. Semin. Cell. Dev. Biol., 235, 659–667CrossRefGoogle Scholar
  16. 16.
    Meluzzi, D. and Arya, G. (2013) Recovering ensembles of chromatin conformations from contact probabilities. Nucleic Acids Res., 41, 63–75CrossRefPubMedGoogle Scholar
  17. 17.
    Tolhuis, B., Palstra, R. J., Splinter, E., Grosveld, F. and de Laat, W. (2002) Looping and interaction between hypersensitive sites in the active ß-globin locus. Mol. Cell, 10, 1453–1465CrossRefPubMedGoogle Scholar
  18. 18.
    Brackley, C. A., Brown, J. M., Waithe, D., Babbs, C., Davies, J., Hughes, J. R., Buckle, V. J. and Marenduzzo, D. (2016) Predicting the three-dimensional folding of cis-regulatory regions in mammalian genomes using bioinformatic data and polymer models. Genome Biol., 17, 59CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Rosa, A. and Everaers, R. (2008) Structure and dynamics of interphase chromosomes. PLoS Comput. Biol., 4, e1000153CrossRefGoogle Scholar
  20. 20.
    Tokuda, N., Terada, T. P. and Sasai, M. (2012) Dynamical modeling of three-dimensional genome organization in interphase budding yeast. Biophys. J., 102, 296–304CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Fudenberg, G. and Mirny, L. A. (2012) Higher-order chromatin structure: bridging physics and biology. Curr. Opin. Genet. Dev., 22, 115–124CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Tark-Dame, M., van Driel, R. and Heermann, D. W. (2011) Chromatin folding—from biology to polymer models and back. J. Cell Sci., 124, 839–845CrossRefPubMedGoogle Scholar
  23. 23.
    Mateos-Langerak, J., Bohn, M., de Leeuw, W., Giromus, O., Manders, E. M., Verschure, P. J., Indemans, M. H., Gierman, H. J., Heermann, D. W., van Driel, R., et al. (2009) Spatially confined folding of chromatin in the interphase nucleus. Proc. Natl. Acad. Sci. USA, 106, 3812–3817CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Marko, J. F. and Siggia, E. D. (1997) Polymer models of meiotic and mitotic chromosomes. Mol. Biol. Cell, 8, 2217–2231CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Göndör, A. and Ohlsson, R. (2009) Chromosome crosstalk in three dimensions. Nature, 461, 212–217CrossRefPubMedGoogle Scholar
  26. 26.
    Kadauke, S. and Blobel, G. A. (2009) Chromatin loops in gene regulation. Biochim. Biophys. Acta, 1789, 17–25CrossRefPubMedGoogle Scholar
  27. 27.
    Bohn, M. and Heermann, D. W. (2010) Diffusion-driven looping provides a consistent framework for chromatin organization. PLoS One, 5, e12218CrossRefGoogle Scholar
  28. 28.
    Nicodemi, M., Panning, B. and Prisco, A. (2008) A thermodynamic switch for chromosome colocalization. Genetics, 179, 717–721CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Alipour, E. and Marko, J. F. (2012) Self-organization of domain structures by DNA-loop-extruding enzymes. Nucleic Acids Res., 40, 11202–11212CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Grosberg, A. Iu., Nechaev, S. K. and Shakhnovich, E. I. (1988) The role of topological limitations in the kinetics of homopolymer collapse and self-assembly of biopolymers. Biofizika, 33, 247–253PubMedGoogle Scholar
  31. 31.
    Nicodemi, M., Panning, B. and Prisco, A. (2008) A thermodynamic switch for chromosome colocalization. Genetics, 179, 717–721CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Barbieri, M., Chotalia, M., Fraser, J., Lavitas, L. M., Dostie, J., Pombo, A. and Nicodemi, M. (2012) Complexity of chromatin folding is captured by the strings and binders switch model. Proc. Natl. Acad. Sci. USA, 109, 16173–16178CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Goloborodko, A., Marko, J. F. and Mirny, L. A. (2016) Chromosome compaction by active loop extrusion. Biophys. J., 110, 2162–2168CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Rao, S. S., 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) A 3D map of the human genome at kilobase resolution reveals principles of chromatin looping. Cell, 159, 1665–1680CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Fudenberg, G., Imakaev, M., Lu, C., Goloborodko, A., Abdennur, N., Mimy, L.A. (2015) Formation of chromosomal domains by loop extrusion. Cell Rep., 15, 2038–2049CrossRefGoogle Scholar
  36. 36.
    Gruber, S. (2014) Multilayer chromosome organization through DNA bending, bridging and extrusion. Curr. Opin. Microbiol., 22, 102–110CrossRefPubMedGoogle Scholar
  37. 37.
    Simonis, M., Klous, P., Splinter, E., Moshkin, Y., Willemsen, R., de Wit, E., van Steensel, B. and de Laat, W. (2006) Nuclear organization of active and inactive chromatin domains uncovered by chromosome conformation capture-on-chip (4C). Nat. Genet., 38, 1348–1354CrossRefPubMedGoogle Scholar
  38. 38.
    Dostie, J., Richmond, T. A., Arnaout, R. A., Selzer, R. R., Lee, W. L., Honan, T. A., Rubio, E. D., Krumm, A., Lamb, J., Nusbaum, C., et al. (2006) Chromosome Conformation Capture Carbon Copy (5C): a massively parallel solution for mapping interactions between genomic elements. Genome Res., 16, 1299–1309CrossRefPubMedPubMedCentralGoogle Scholar
  39. 39.
    Zhang, J., Poh, H. M., Peh, S. Q., Sia, Y. Y., Li, G., Mulawadi, F. H., Goh, Y., Fullwood, M. J., Sung, W. K., Ruan, X., et al. (2012) ChIAPET analysis of transcriptional chromatin interactions. Methods, 58, 289–299CrossRefPubMedGoogle Scholar
  40. 40.
    Denker, A. and de Laat, W. (2016) The second decade of 3C technologies: detailed insights into nuclear organization. Genes Dev., 30, 1357–1382CrossRefPubMedPubMedCentralGoogle Scholar
  41. 41.
    Duan, Z., Andronescu, M., Schutz, K., McIlwain, S., Kim, Y. J., Lee, C., Shendure, J., Fields, S., Blau, C. A. and Noble, W. S. (2010) A three-dimensional model of the yeast genome. Nature, 465, 363–367CrossRefPubMedPubMedCentralGoogle Scholar
  42. 42.
    Sexton, T., Yaffe, E., Kenigsberg, E., Bantignies, F., Leblanc, B., Hoichman, M., Parrinello, H., Tanay, A. and Cavalli, G. (2012) Threedimensional folding and functional organization principles of the Drosophila genome. Cell, 148, 458–472CrossRefPubMedGoogle Scholar
  43. 43.
    Zhang, Y., McCord, R. P., Ho, Y. J., Lajoie, B. R., Hildebrand, D. G., Simon, A. C., Becker, M. S., Alt, F. W. and Dekker, J. (2012) Spatial organization of the mouse genome and its role in recurrent chromosomal translocations. Cell, 148, 908–921CrossRefPubMedPubMedCentralGoogle Scholar
  44. 44.
    Hübner, M. R. and Spector, D. L. (2010) Chromatin dynamics. Annu. Rev. Biophys., 39, 471–489CrossRefPubMedPubMedCentralGoogle Scholar
  45. 45.
    Lesne, A., Riposo, J., Roger, P., Cournac, A. and Mozziconacci, J. (2014) 3D genome reconstruction from chromosomal contacts. Nat. Methods, 11, 1141–1143CrossRefPubMedGoogle Scholar
  46. 46.
    Zhang, Z., Li, G., Toh, K. C. and Sung, W. K. (2013) 3D chromosome modeling with semi-definite programming and Hi-C data. J. Comput. Biol., 20, 831–846CrossRefPubMedGoogle Scholar
  47. 47.
    Varoquaux, N., Ay, F., Noble, W. S. and Vert, J. P. (2014) A statistical approach for inferring the 3D structure of the genome. Bioinformatics, 30, i26–i33CrossRefPubMedPubMedCentralGoogle Scholar
  48. 48.
    Peng, C., Fu, L. Y., Dong, P. F., Deng, Z. L., Li, J. X., Wang, X. T. and Zhang, H. Y. (2013) The sequencing bias relaxed characteristics of Hi-C derived data and implications for chromatin 3D modeling. Nucleic Acids Res., 41, e183CrossRefGoogle Scholar
  49. 49.
    Ba, D. and Marti-Renom, M. A. (2012) Genome structure determination via 3C-based data integration by the Integrative Modeling Platform. Methods, 58, 300–306CrossRefGoogle Scholar
  50. 50.
    Zou, C., Zhang, Y. and Ouyang, Z. (2016) HSA: integrating multi-track Hi-C data for genome-scale reconstruction of 3D chromatin structure. Genome Biol., 17, 40CrossRefPubMedPubMedCentralGoogle Scholar
  51. 51.
    Nowotny, J., Ahmed, S., Xu, L., Oluwadare, O., Chen, H., Hensley, N., Trieu, T., Cao, R. and Cheng, J. (2015) Iterative reconstruction of threedimensional models of human chromosomes from chromosomal contact data. BMC Bioinformatics, 16, 338CrossRefPubMedPubMedCentralGoogle Scholar
  52. 52.
    Trieu, T. and Cheng, J. (2014) Large-scale reconstruction of 3D structures of human chromosomes from chromosomal contact data. Nucleic Acids Res., 42, e52CrossRefGoogle Scholar
  53. 53.
    Serra, F., Di Stefano, M., Spill, Y. G., Cuartero, Y., Goodstadt, M., Ba, D. and Marti-Renom, M. A. (2015) Restraint-based three-dimensional modeling of genomes and genomic domains. FEBS Lett., 589, 2987–2995CrossRefPubMedGoogle Scholar
  54. 54.
    Yaffe, E. and Tanay, A. (2011) Probabilistic modeling of Hi-C contact maps eliminates systematic biases to characterize global chromosomal architecture. Nat. Genet., 43, 1059–1065CrossRefPubMedGoogle Scholar
  55. 55.
    Wang, S., Xu, J. and Zeng, J. (2015) Inferential modeling of 3D chromatin structure. Nucleic Acids Res., 43, e54CrossRefGoogle Scholar
  56. 56.
    Tjong, H., Li, W., Kalhor, R., Dai, C., Hao, S., Gong, K., Zhou, Y., Li, H., Zhou, X. J., Le Gros, M. A., et al. (2016) Population-based 3D genome structure analysis reveals driving forces in spatial genome organization. Proc. Natl. Acad. Sci. USA, 113, e1663–E1672CrossRefGoogle Scholar
  57. 57.
    Rousseau, M., Fraser, J., Ferraiuolo, M. A., Dostie, J. and Blanchette, M. (2011) Three-dimensional modeling of chromatin structure from interaction frequency data using Markov chain Monte Carlo sampling. BMC Bioinformatics, 12, 414CrossRefPubMedPubMedCentralGoogle Scholar
  58. 58.
    Hu, M., Deng, K., Qin, Z., Dixon, J., Selvaraj, S., Fang, J., Ren, B. and Liu, J. S. (2013) Bayesian inference of spatial organizations of chromosomes. PLoS Comput. Biol., 9, e1002893CrossRefGoogle Scholar
  59. 59.
    He, C., Wang, X. and Zhang, M. Q. (2014) Nucleosome eviction and multiple co-factor binding predict estrogen-receptor-alpha-associated long-range interactions. Nucleic Acids Res., 42, 6935–6944CrossRefPubMedPubMedCentralGoogle Scholar
  60. 60.
    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, 376–380CrossRefPubMedPubMedCentralGoogle Scholar
  61. 61.
    Ho, J. W., Jung, Y. L., Liu, T., Alver, B. H., Lee, S., Ikegami, K., Sohn, K. A., Minoda, A., Tolstorukov, M. Y., Appert, A., et al. (2014) Comparative analysis of metazoan chromatin organization. Nature, 512, 449–452CrossRefPubMedPubMedCentralGoogle Scholar
  62. 62.
    Fortin, J. P. and Hansen, K. D. (2015) Reconstructing A/B compartments as revealed by Hi-C using long-range correlations in epigenetic data. Genome Biol., 16, 180CrossRefPubMedPubMedCentralGoogle Scholar
  63. 63.
    Huang, J., Marco, E., Pinello, L. and Yuan, G. C. (2015) Predicting chromatin organization using histone marks. Genome Biol., 16, 162CrossRefPubMedPubMedCentralGoogle Scholar
  64. 64.
    Zhang, Z. and Zhang, M. Q. (2011) Histone modification profiles are predictive for tissue/cell-type specific expression of both protein-coding and microRNA genes. BMC Bioinformatics, 12, 155CrossRefPubMedPubMedCentralGoogle Scholar
  65. 65.
    Wang, Z., Zang, C., Rosenfeld, J. A., Schones, D. E., Barski, A., Cuddapah, S., Cui, K., Roh, T. Y., Peng,W., Zhang, M. Q., et al. (2008) Combinatorial patterns of histone acetylations and methylations in the human genome. Nat. Genet., 40, 897–903CrossRefPubMedPubMedCentralGoogle Scholar
  66. 66.
    Karlic, R., Chung, H. R., Lasserre, J., Vlahovicek, K. and Vingron, M. (2010) Histone modification levels are predictive for gene expression. Proc. Natl. Acad. Sci. USA, 107, 2926–2931CrossRefPubMedPubMedCentralGoogle Scholar
  67. 67.
    Allis, C. D., Jenuwein, T., Reinberg, D., Caparros, M. (2015) Epigenetics. New York: Cold Spring Harbor Laboratory PressGoogle Scholar
  68. 68.
    Zhu, Y., Chen, Z., Zhang, K., Wang, M., Medovoy, D., Whitaker, J.W., Ding, B., Li, N., Zheng, L. and Wang, W. (2016) Constructing 3D interaction maps from 1D epigenomes. Nat. Commun., 7, 10812CrossRefPubMedPubMedCentralGoogle Scholar
  69. 69.
    Chen, Y., Wang, Y., Xuan, Z., Chen, M. and Zhang, M. Q. (2016) De novo deciphering three-dimensional chromatin interaction and topological domains by wavelet transformation of epigenetic profiles. Nucleic Acids Res., 44, e106CrossRefGoogle Scholar
  70. 70.
    Whalen, S., Truty, R. M. and Pollard, K. S. (2016) Enhancer-promoter interactions are encoded by complex genomic signatures on looping chromatin. Nat. Genet., 48, 488–496CrossRefPubMedPubMedCentralGoogle Scholar
  71. 71.
    The ENCODE Project Consortium. (2012) An integrated encyclopedia of DNA elements in the human genome. Nature, 489, 57–74CrossRefPubMedCentralGoogle Scholar
  72. 72.
    Kornberg, R. D. and Stryer, L. (1988) Statistical distributions of nucleosomes: nonrandom locations by a stochastic mechanism. Nucleic Acids Res., 16, 6677–6690CrossRefPubMedPubMedCentralGoogle Scholar
  73. 73.
    Kalhor, R., Tjong, H., Jayathilaka, N., Alber, F. and Chen, L. (2011) Genome architectures revealed by tethered chromosome conformation capture and population-based modeling. Nat. Biotechnol., 30, 90–98CrossRefPubMedPubMedCentralGoogle Scholar
  74. 74.
    Giorgetti, L., Galupa, R., Nora, E. P., Piolot, T., Lam, F., Dekker, J., Tiana, G. and Heard, E. (2014) Predictive polymer modeling reveals coupled fluctuations in chromosome conformation and transcription. Cell, 157, 950–963CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Higher Education Press and Springer-Verlag GmbH 2016

Authors and Affiliations

  1. 1.CAS Key Laboratory of Genome Sciences and Information, Beijing Institute of GenomicsChinese Academy of SciencesBeijingChina

Personalised recommendations