© The Institution of Engineering and Technology
Epigenetics is emerging as a fundamentally important area of biological and medical research that has implications for our understanding of human diseases including cancer, autoimmune and neuropsychiatric disorders. In the context of recent efforts on personalised medicine, a novel research direction is concerned with identification of intra-individual epigenetic variation linked to disease predisposition and development, i.e. epigenome-wide association studies. A computational model has been developed to describe the dynamics and structure of human intestinal crypts and to perform a comparative analysis on aberrant DNA methylation level induced in these during cancer initiation. The crypt framework, AgentCrypt, is an agent-based model of crypt dynamics, which handles intra- and inter-dependencies. In addition, the AgentCrypt model is used to investigate the effect of a set of potential inhibitors with respect to methylation modification in intestinal tissue during initiation of disease. Methylation level decrease over a relatively short period of 90 days is marked for the colon compared to the small intestine, although similar alterations are induced in both tissues. In addition, inhibitor effect is notable for abnormal crypt groups, with largest average methylation differences observed ≈0.75% lower in the colon and ≈0.79% lower in the small intestine with inhibitor present.
References
-
-
1)
-
30. Potten, C.S., Booth, C., Hargreaves, D.: ‘The small intestine as a model for evaluating adult tissue stem cell drug targets1’, Cell Prolif., 2003, 36, (3), pp. 115–129 (doi: 10.1046/j.1365-2184.2003.00264.x).
-
2)
-
23. Roznovat, I.A., Ruskin, H.J.: ‘Methylation inhibitors and carcinogens in an agent-based model for colon crypt dynamics during cancer development’. Modelling Symp. (EMS), 2013 European, 2013, pp. 152–157.
-
3)
-
8. Azad, N., Zahnow, C.A., Rudin, C.M., Baylin, S.B.: ‘The future of epigenetic therapy in solid tumours – lessons from the past’, Nat. Rev. Clin. Oncol., 2013, 10, (5), pp. 256–266 (doi: 10.1038/nrclinonc.2013.42).
-
4)
-
46. De Matteis, G., Graudenzi, A., Antoniotti, M.: ‘A review of spatial computational models for multi-cellular systems, with regard to intestinal crypts and colorectal cancer development’, J. Math. Biol., 2013, 66, (7), pp. 1409–1462 (doi: 10.1007/s00285-012-0539-4).
-
5)
-
45. Pitt-Francis, J., Pathmanathan, P., Bernabeu, M.O., et al: ‘Chaste: a test-driven approach to software development for biological modelling’, Comput. Phys. Commun., 2009, 180, (12), pp. 2452–2471 (doi: 10.1016/j.cpc.2009.07.019).
-
6)
-
27. Perrin, D., Ruskin, H.J., Niwa, T.: ‘Cell type-dependent, infection-induced, aberrant DNA methylation in gastric cancer’, J. Theor. Biol., 2010, 264, (2), pp. 570–577 (doi: 10.1016/j.jtbi.2010.02.040).
-
7)
-
40. Perrin, D., Ruskin, H.J., Burns, J., Crane, M.: ‘An agent-based approach to immune modelling’. Computational Science and its Applications-ICCSA 2006, 2006, pp. 612–621.
-
8)
-
34. Kim, J.Y., Siegmund, K.D., Tavaré, S., Shibata, D.: ‘Age-related human small intestine methylation: evidence for stem cell niches’, BMC Med., 2005, 3, (1), pp. 3–10 (doi: 10.1186/1741-7015-3-10).
-
9)
-
7. Herman, J.G., Baylin, S.B.: ‘Gene silencing in cancer in association with promoter hypermethylation’, N. Engl. J. Med., 2003, 349, (21), pp. 2042–2054 (doi: 10.1056/NEJMra023075).
-
10)
-
24. Roznovat, I.A., Ruskin, H.J.: ‘A computational analysis on methylation inhibition during intestinal cancer initiation’. 2014 IEEE Int. Conf. on Bioinformatics and Biomedicine (BIBM), 2014, pp. 22–29.
-
11)
-
39. Segovia-Juarez, J.L., Ganguli, S., Kirschner, D.: ‘Identifying control mechanisms of granuloma formation during M. tuberculosis infection using an agent-based model’, J. Theor. Biol., 2004, 231, (3), pp. 357–376 (doi: 10.1016/j.jtbi.2004.06.031).
-
12)
-
50. Lay, F.D., Triche, T.J., Tsai, Y.C., et al: ‘Reprogramming of the human intestinal epigenome by surgical tissue transposition’, Genome Res., 2014, 24, (4), pp. 545–553 (doi: 10.1101/gr.166439.113).
-
13)
-
33. Umar, S.: ‘Intestinal stem cells’, Curr. Gastroenterol. Rep., 2010, 12, (5), pp. 340–348 (doi: 10.1007/s11894-010-0130-3).
-
14)
-
4. Carey, N., Marques, C.J., Reik, W.: ‘DNA demethylases: a new epigenetic frontier in drug discovery’, Drug Discov. Today, 2011, 16, (15), pp. 683–690 (doi: 10.1016/j.drudis.2011.05.004).
-
15)
-
20. Bock, C.: ‘Analysing and interpreting DNA methylation data’, Nat. Rev. Genet., 2012, 13, (10), pp. 705–719 (doi: 10.1038/nrg3273).
-
16)
-
19. Shenker, N.S., Polidoro, S., van Veldhoven, K., et al: ‘Epigenome-wide association study in the European prospective investigation into cancer and nutrition (EPIC-Turin) identifies novel genetic loci associated with smoking’, Hum. Mol. Genet., 2012, pp. 843–851.
-
17)
-
25. Vaiopoulos, A.G., Kostakis, I.D., Koutsilieris, M., Papavassiliou, A.G.: ‘Colorectal cancer stem cells’, Stem Cells, 2012, 30, (3), pp. 363–371 (doi: 10.1002/stem.1031).
-
18)
-
32. Sancho, E., Batlle, E., Clevers, H.: ‘Live and let die in the intestinal epithelium’, Curr. Opin. Cell Biol., 2003, 15, (6), pp. 763–770 (doi: 10.1016/j.ceb.2003.10.012).
-
19)
-
31. Clevers, H.C., Bevins, C.L.: ‘Paneth cells: maestros of the small intestinal crypts’, Annu. Rev. Physiol., 2013, 75, pp. 289–311 (doi: 10.1146/annurev-physiol-030212-183744).
-
20)
-
1. Allis, C.D., Jenuwein, T., Reinberg, D., Caparros, M.-L.: ‘Epigenetics’, 2007.
-
21)
-
38. Ruskin, H.J., Pandey, R.B., Liu, Y.: ‘Viral load and stochastic mutation in a Monte Carlo simulation of HIV’, Phys. Stat. Mech. Appl., 2002, 311, (1), pp. 213–220 (doi: 10.1016/S0378-4371(02)00832-4).
-
22)
-
21. Brueckner, B., Boy, R.G., Siedlecki, P., et al: ‘Epigenetic reactivation of tumor suppressor genes by a novel small-molecule inhibitor of human DNA methyltransferases’, Cancer Res., 2005, 65, (14), pp. 6305–6311 (doi: 10.1158/0008-5472.CAN-04-2957).
-
23)
-
42. Barat, A., Ruskin, H.J., Crane, M.: ‘Probabilistic models for drug dissolution. Part 1. Review of Monte Carlo and stochastic cellular automata approaches’, Simul. Model. Pract. Theory, 2006, 14, (7), pp. 843–856 (doi: 10.1016/j.simpat.2006.01.004).
-
24)
-
3. Bird, A.: ‘DNA methylation patterns and epigenetic memory’, Genes Dev., 2002, 16, (1), pp. 6–21 (doi: 10.1101/gad.947102).
-
25)
-
10. Abel, T., Zukin, R.S.: ‘Epigenetic targets of HDAC inhibition in neurodegenerative and psychiatric disorders’, Curr. Opin. Pharmacol., 2008, 8, (1), pp. 57–64 (doi: 10.1016/j.coph.2007.12.002).
-
26)
-
6. Ghildiyal, M., Zamore, P.D.: ‘Small silencing RNAs: an expanding universe’, Nat. Rev. Genet., 2009, 10, (2), pp. 94–108 (doi: 10.1038/nrg2504).
-
27)
-
51. Jin, G., Ramanathan, V., Quante, M., et al: ‘Inactivating cholecystokinin-2 receptor inhibits progastrin-dependent colonic crypt fission, proliferation, and colorectal cancer in mice’, J. Clin. Invest., 2009, 119, (9), pp. 2691–2701.
-
28)
-
43. Bezbradica, M., Ruskin, H.J., Crane, M.: ‘Probabilistic pharmaceutical modelling: a comparison between synchronous and asynchronous cellular automata’. Parallel Processing and Applied Mathematics, 2014, pp. 699–710.
-
29)
-
49. Naumov, V.A., Generozov, E.V., Zaharjevskaya, N.B., et al: ‘Genome-scale analysis of DNA methylation in colorectal cancer using Infinium HumanMethylation450 BeadChips’, Epigenetics, 2013, 8, (9), pp. 921–934 (doi: 10.4161/epi.25577).
-
30)
-
12. Hatzimichael, E., Crook, T.: ‘Cancer epigenetics: new therapies and new challenges’, J. Drug Deliv., 2013, 2013, pp. 1–9 (doi: 10.1155/2013/529312).
-
31)
-
35. Brittan, M., Wright, N.A.: ‘Stem cell in gastrointestinal structure and neoplastic development’, Gut, 2004, 53, (6), pp. 899–910 (doi: 10.1136/gut.2003.025478).
-
32)
-
17. Mill, J., Heijmans, B.T.: ‘From promises to practical strategies in epigenetic epidemiology’, Nat. Rev. Genet., 2013, 14, (8), pp. 585–594 (doi: 10.1038/nrg3405).
-
33)
-
14. Siegel, R., Ma, J., Zou, Z., Jemal, A.: ‘Cancer statistics, 2014’, CA. Cancer J. Clin., 2014, 64, (1), pp. 9–29 (doi: 10.3322/caac.21208).
-
34)
-
18. Petersen, A.-K., Zeilinger, S., Kastenmüller, G., et al: ‘Epigenetics meets metabolomics: an epigenome-wide association study with blood serum metabolic traits’, Hum. Mol. Genet., 2014, 23, (2), pp. 534–545 (doi: 10.1093/hmg/ddt430).
-
35)
-
5. Jenuwein, T., Allis, C.D.: ‘Translating the histone code’, Science, 2001, 293, (5532), pp. 1074–1080 (doi: 10.1126/science.1063127).
-
36)
-
47. Pogribny, I.P., Vanyushin, B.F.: ‘Age-related genomic hypomethylation’. Epigenetics of Aging, 2010, pp. 11–27.
-
37)
-
53. Roznovăţ, I.A., Ruskin, H.J.: ‘A computational model for genetic and epigenetic signals in colon cancer’, Interdiscip. Sci. Comput. Life Sci., 2013, 5, (3), pp. 175–186 (doi: 10.1007/s12539-013-0172-y).
-
38)
-
29. Humphries, A., Wright, N.A.: ‘Colonic crypt organization and tumorigenesis’, Nat. Rev. Cancer, 2008, 8, (6), pp. 415–424 (doi: 10.1038/nrc2392).
-
39)
-
26. Reya, T., Clevers, H.: ‘Wnt signalling in stem cells and cancer’, Nature, 2005, 434, (7035), pp. 843–850 (doi: 10.1038/nature03319).
-
40)
-
28. Johannes, F., Porcher, E., Teixeira, F.K., et al: ‘Assessing the impact of transgenerational epigenetic variation on complex traits’, PLoS Genet., 2009, 5, (6), p. e1000530 (doi: 10.1371/journal.pgen.1000530).
-
41)
-
11. Urdinguio, R.G., Sanchez-Mut, J.V., Esteller, M.: ‘Epigenetic mechanisms in neurological diseases: genes, syndromes, and therapies’, Lancet Neurol., 2009, 8, (11), pp. 1056–1072 (doi: 10.1016/S1474-4422(09)70262-5).
-
42)
-
22. Fernandez, A.F., Assenov, Y., Martin-Subero, J.I., et al: ‘A DNA methylation fingerprint of 1628 human samples’, Genome Res., 2012, 22, (2), pp. 407–419 (doi: 10.1101/gr.119867.110).
-
43)
-
41. Perrin, D., Ruskin, H.J., Crane, M.: ‘An agent-based approach to immune modelling: priming individual response’, Trans. Eng. Comput. Technol., 2006, 17, pp. 80–86.
-
44)
-
13. Ferlay, J., Soerjomataram, I., Ervik, M., et al: ‘GLOBOCAN 2012 v1. 0, cancer incidence and mortality worldwide: IARC CancerBase No. 11. Lyon, France: International Agency for Research on Cancer; 2013’. Visit Httpglobocan Iarc Fr, 2014.
-
45)
-
9. Alegría-Torres, J.A., Baccarelli, A., Bollati, V.: ‘Epigenetics and lifestyle’, Epigenomics, 2011, 3, (3), pp. 267–277 (doi: 10.2217/epi.11.22).
-
46)
-
36. Vinken, M., De Rop, E., Decrock, E., et al: ‘Epigenetic regulation of gap junctional intercellular communication: more than a way to keep cells quiet?’, Biochim. Biophys. Acta BBA, Rev. Cancer, 2009, 1795, (1), pp. 53–61 (doi: 10.1016/j.bbcan.2008.08.002).
-
47)
-
52. Yoo, C.B., Jones, P.A.: ‘Epigenetic therapy of cancer: past, present and future’, Nat. Rev. Drug Discov., 2006, 5, (1), pp. 37–50 (doi: 10.1038/nrd1930).
-
48)
-
37. Mannion, R., Ruskin, H., Pandey, R.B.: ‘Effect of mutation on helper T-cells and viral population: a computer simulation model for HIV’, Theory Biosci., 2000, 119, (1), pp. 10–19 (doi: 10.1007/s12064-000-0002-8).
-
49)
-
2. Baylin, S.B., Jones, P.A.: ‘A decade of exploring the cancer epigenome – biological and translational implications’, Nat. Rev. Cancer, 2011, 11, (10), pp. 726–734 (doi: 10.1038/nrc3130).
-
50)
-
54. Jones, P.A., Baylin, S.B.: ‘The fundamental role of epigenetic events in cancer’, Nat. Rev. Genet., 2002, 3, (6), pp. 415–428.
-
51)
-
44. Hwang, M., Garbey, M., Berceli, S.A., Tran-Son-Tay, R.: ‘Rule-based simulation of multi-cellular biological systems – a review of modeling techniques’, Cell. Mol. Bioeng., 2009, 2, (3), pp. 285–294 (doi: 10.1007/s12195-009-0078-2).
-
52)
-
48. Meissner, A.: ‘Epigenetic modifications in pluripotent and differentiated cells’, Nat. Biotechnol., 2010, 28, (10), pp. 1079–1088 (doi: 10.1038/nbt.1684).
-
53)
-
16. Rakyan, V.K., Down, T.A., Balding, D.J., Beck, S.: ‘Epigenome-wide association studies for common human diseases’, Nat. Rev. Genet., 2011, 12, (8), pp. 529–541 (doi: 10.1038/nrg3000).
-
54)
-
15. Verma, M.: ‘Epigenome-wide association studies (EWAS) in cancer’, Curr. Genomics, 2012, 13, (4), pp. 308–313 (doi: 10.2174/138920212800793294).
http://iet.metastore.ingenta.com/content/journals/10.1049/iet-syb.2015.0048
Related content
content/journals/10.1049/iet-syb.2015.0048
pub_keyword,iet_inspecKeyword,pub_concept
6
6