Computational inference of physical spatial organization of eukaryotic genomes

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.

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

Graphical abstract

Keywords

3D genome / models / simulation

References

[1] Dillon, N. (2008) The impact of gene location in the nucleus on transcriptional regulation. Dev. Cell, 15, 182–186

[2] Miele, A. and Dekker, J. (2008) Long-range chromosomal interactions and gene regulation. Mol. Biosyst., 4, 1046–1057

[3] Dekker, J., Rippe, K., Dekker, M., Kleckner, N. (2002) Capturing chromosome conformation. Science, 295,1306–1311

[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. (2009) Comprehensive mapping of long-range interactions reveals folding principles of the human genome. Science, 326, 289–293

[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: Springer

[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, 376–380

[7] Zhu, P. and Li, G. (2016) Structural insights of nucleosome and the 30-nm chromatin fiber. Curr. Opin. Struct. Biol., 36, 106–115

[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, 948–953

[9] Tang, Z., Luo, O. J., Li, X., Zheng, M., Zhu, J. J., Szalaj, P., Trzaskoma, P., Magalska, A., Wlodarczyk, J., Ruszczycki, B., (2015) CTCF-mediated human 3D genome architecture reveals chromatin topology for transcription. Cell, 163, 1611–1627

[10] Bickmore, W. A. (2013) The spatial organization of the human genome. Annu. Rev. Genomics Hum. Genet., 14, 67–84

[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, 1111–1118

[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, 780–788

[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, 825–847

[14] Gr�nbech-Jensen, N., Mashl, R. J., Bruinsma, R. F. and Gelbart, W. M. (1997) Counterion-induced attraction between rigid polyelectrolytes. Phys. Rev. Lett., 78, 2477–2480

[15] Langowski, J. and Heermann, D. W. (2007) Computational modeling of the chromatin fiber. Semin. Cell. Dev. Biol., 235, 659–667

[16] Meluzzi, D. and Arya, G. (2013) Recovering ensembles of chromatin conformations from contact probabilities. Nucleic Acids Res., 41, 63–75

[17] Tolhuis, B., Palstra, R. J., Splinter, E., Grosveld, F. and de Laat, W. (2002) Looping and interaction between hypersensitive sites in the active β-globin locus. Mol. Cell, 10, 1453–1465

[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, 59

[19] Rosa, A. and Everaers, R. (2008) Structure and dynamics of interphase chromosomes. PLoS Comput. Biol., 4, e1000153

[20] Tokuda, N., Terada, T. P. and Sasai, M. (2012) Dynamical modeling of three-dimensional genome organization in interphase budding yeast. Biophys. J., 102, 296–304

[21] Fudenberg, G. and Mirny, L. A. (2012) Higher-order chromatin structure: bridging physics and biology. Curr. Opin. Genet. Dev., 22, 115–124

[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, 839–845

[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., (2009) Spatially confined folding of chromatin in the interphase nucleus. Proc. Natl. Acad. Sci. USA, 106, 3812–3817

[24] Marko, J. F. and Siggia, E. D. (1997) Polymer models of meiotic and mitotic chromosomes. Mol. Biol. Cell, 8, 2217–2231

[25] Göndör, A. and Ohlsson, R. (2009) Chromosome crosstalk in three dimensions. Nature, 461, 212–217

[26] Kadauke, S. and Blobel, G. A. (2009) Chromatin loops in gene regulation. Biochim. Biophys. Acta, 1789, 17–25

[27] Bohn, M. and Heermann, D. W. (2010) Diffusion-driven looping provides a consistent framework for chromatin organization. PLoS One, 5, e12218

[28] Nicodemi, M., Panning, B. and Prisco, A. (2008) A thermodynamic switch for chromosome colocalization. Genetics, 179, 717–721

[29] Alipour, E. and Marko, J. F. (2012) Self-organization of domain structures by DNA-loop-extruding enzymes. Nucleic Acids Res., 40, 11202–11212

[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, 247–253

[31] Nicodemi, M., Panning, B. and Prisco, A. (2008) A thermodynamic switch for chromosome colocalization. Genetics, 179, 717–721

[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, 16173–16178

[33] Goloborodko, A., Marko, J. F. and Mirny, L. A. (2016) Chromosome compaction by active loop extrusion. Biophys. J., 110, 2162–2168

[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., (2014) A 3D map of the human genome at kilobase resolution reveals principles of chromatin looping. Cell, 159, 1665–1680

[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, 2038–2049

[36] Gruber, S. (2014) Multilayer chromosome organization through DNA bending, bridging and extrusion. Curr. Opin. Microbiol., 22, 102–110

[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, 1348–1354

[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., (2006) Chromosome Conformation Capture Carbon Copy (5C): a massively parallel solution for mapping interactions between genomic elements. Genome Res., 16, 1299–1309

[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., (2012) ChIA-PET analysis of transcriptional chromatin interactions. Methods, 58, 289–299

[40] Denker, A. and de Laat, W. (2016) The second decade of 3C technologies: detailed insights into nuclear organization. Genes Dev., 30, 1357–1382

[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, 363–367

[42] 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

[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, 908–921

[44] Hübner, M. R. and Spector, D. L. (2010) Chromatin dynamics. Annu. Rev. Biophys., 39, 471–489

[45] Lesne, A., Riposo, J., Roger, P., Cournac, A. and Mozziconacci, J. (2014) 3D genome reconstruction from chromosomal contacts. Nat. Methods, 11, 1141–1143

[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, 831–846

[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–i33

[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, e183

[49] Ba�, D. and Marti-Renom, M. A. (2012) Genome structure determination via 3C-based data integration by the Integrative Modeling Platform. Methods, 58, 300–306

[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, 40

[51] Nowotny, J., Ahmed, S., Xu, L., Oluwadare, O., Chen, H., Hensley, N., Trieu, T., Cao, R. and Cheng, J. (2015) Iterative reconstruction of three-dimensional models of human chromosomes from chromosomal contact data. BMC Bioinformatics, 16, 338

[52] Trieu, T. and Cheng, J. (2014) Large-scale reconstruction of 3D structures of human chromosomes from chromosomal contact data. Nucleic Acids Res., 42, e52

[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, 2987–2995

[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, 1059–1065

[55] Wang, S., Xu, J. and Zeng, J. (2015) Inferential modeling of 3D chromatin structure. Nucleic Acids Res., 43, e54.

[56] Tjong, H., Li, W., Kalhor, R., Dai, C., Hao, S., Gong, K., Zhou, Y., Li, H., Zhou, X. J., Le Gros, M. A., (2016) Population-based 3D genome structure analysis reveals driving forces in spatial genome organization. Proc. Natl. Acad. Sci. USA, 113, E1663–E1672

[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, 414

[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, e1002893

[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, 6935–6944

[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– 380

[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., (2014) Comparative analysis of metazoan chromatin organization. Nature, 512, 449–452

[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, 180

[63] Huang, J., Marco, E., Pinello, L. and Yuan, G. C. (2015) Predicting chromatin organization using histone marks. Genome Biol., 16, 162

[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, 155

[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., (2008) Combinatorial patterns of histone acetylations and methylations in the human genome. Nat. Genet., 40, 897–903

[66] Karlić, 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, 2926–2931

[67] Allis, C. D., Jenuwein, T., Reinberg, D., Caparros, M. (2015) Epigenetics. New York: Cold Spring Harbor Laboratory Press

[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, 10812

[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, e106

[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, 488–496

[71] The ENCODE Project Consortium. (2012) An integrated encyclopedia of DNA elements in the human genome. Nature, 489, 57–74

[72] Kornberg, R. D. and Stryer, L. (1988) Statistical distributions of nucleosomes: nonrandom locations by a stochastic mechanism. Nucleic Acids Res., 16, 6677–6690

[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, 90–98

[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, 950–963

ACKNOWLEDGEMENTS

We thank Mr. David Martin for the language correction on the manuscript. This work was supported by grants from the National Nature Science Foundation of China (NSFC, 91540114 and 31271398), the National High Technology Development 863 Program of China (2014AA021103), and Special Program for Applied Research on Super Computation of the NSFC-Guangdong Joint Fund (the second phase) to ZZ. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

COMPLIANCE WITH ETHICS GUIDELINES

The authors Bingxiang Xu and Zhihua Zhang declare that they have no conflict of interests.

ƒThis article does not contain any studies with human or animal subjects performed by any of the authors.

Funding

RIGHTS & PERMISSIONS

2016 Higher Education Press and Springer-Verlag Berlin Heidelberg