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The role of DNA methylation in ageing and cancer

  • A. E. Morgan (a1), T. J. Davies (a2) and M. T. Mc Auley (a1)

Abstract

The aim of the present review paper is to survey the literature related to DNA methylation, and its association with cancer and ageing. The review will outline the key factors, including diet, which modulate DNA methylation. Our rationale for conducting this review is that ageing and diseases, including cancer, are often accompanied by aberrant DNA methylation, a key epigenetic process, which is crucial to the regulation of gene expression. Significantly, it has been observed that with age and certain disease states, DNA methylation status can become disrupted. For instance, a broad array of cancers are associated with promoter-specific hypermethylation and concomitant gene silencing. This review highlights that hypermethylation, and gene silencing, of the EN1 gene promoter, a crucial homeobox gene, has been detected in various forms of cancer. This has led to this region being proposed as a potential biomarker for diseases such as cancer. We conclude the review by describing a recently developed novel electrochemical method that can be used to quantify the level of methylation within the EN1 promoter and emphasise the growing trend in the use of electrochemical techniques for the detection of aberrant DNA methylation.

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Corresponding author

*Corresponding author: M. T. Mc Auley, email m.mcauley@chester.ac.uk

References

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1.Lim, DHK & Maher, ER (2010) DNA methylation: a form of epigenetic control of gene expression. Obstetrician Gynaecologist 12, 3742.
2.Stevens, M, Cheng, JB, Li, D et al. (2013) Estimating absolute methylation levels at single-CpG resolution from methylation enrichment and restriction enzyme sequencing methods. Genome Res 23, 15411553.
3.Antequera, F & Bird, A (1993) Number of CpG islands and genes in human and mouse. Proc Natl Acad Sci USA 90, 11995–9.
4.Larsen, F, Gundersen, G, Lopez, R et al. (1992) CpG islands as gene markers in the human genome. Genomics 13, 10951107.
5.Saxonov, S, Berg, P & Brutlag, DL (2006) A genome-wide analysis of CpG dinucleotides in the human genome distinguishes two distinct classes of promoters. Proc Natl Acad Sci USA 103, 14121417.
6.Yang, X, Han, H, De Carvalho, DD et al. (2014) Gene body methylation can alter gene expression and is a therapeutic target in cancer. Cancer Cell 26, 577590.
7.Mendizabal, I & Yi, SV (2016) Whole-genome bisulfite sequencing maps from multiple human tissues reveal novel CpG islands associated with tissue-specific regulation. Hum Mol Genet 25, 6982.
8.Goyal, R, Reinhardt, R & Jeltsch, A (2006) Accuracy of DNA methylation pattern preservation by the Dnmt1 methyltransferase. Nucleic Acids Res 34, 11821188.
9.Okano, M, Bell, DW, Haber, DA et al. (1999) DNA methyltransferases Dnmt3a and Dnmt3b are essential for de novo methylation and mammalian development. Cell 99, 247257.
10.Chédin, F, Lieber, MR & Hsieh, C-L (2002) The DNA methyltransferase-like protein DNMT3L stimulates de novo methylation by Dnmt3a. Proc Natl Acad Sci USA 99, 1691616921.
11.Rasmussen, KD & Helin, K (2016) Role of TET enzymes in DNA methylation, development, and cancer. Genes Dev 30, 733750.
12.Maegawa, S, Lu, Y, Tahara, T et al. (2017) Caloric restriction delays age-related methylation drift. Nat Commun 8, 539.
13.Wilson, VL, Smith, RA, Ma, S et al. (1987) Genomic 5-methyldeoxycytidine decreases with age. J Biol Chem 262, 99489951.
14.Drinkwater, RD, Blake, TJ, Morley, AA et al. (1989) Human lymphocytes aged in vivo have reduced levels of methylation in transcriptionally active and inactive DNA. Mutat Res DNAging 219, 2937.
15.Sun, D, Luo, M, Jeong, M et al. (2014) Epigenomic profiling of young and aged HSCs reveals concerted changes during aging that reinforce self-renewal. Cell Stem Cell 14, 673688.
16.Valentini, E, Zampieri, M, Malavolta, M et al. (2016) Analysis of the machinery and intermediates of the 5hmC-mediated DNA demethylation pathway in aging on samples from the MARK-AGE study. Aging (Albany NY) 8, 18961915.
17.Lopatina, N, Haskell, JF, Andrews, LG et al. (2002) Differential maintenance and de novo methylating activity by three DNA methyltransferases in aging and immortalized fibroblasts. J Cell Biochem 84, 324334.
18.Barlow, DP & Bartolomei, MS (2014) Genomic imprinting in mammals. Cold Spring Harb Perspect Biol 6, a018382.
19.Bartolomei, MS & Ferguson-Smith, AC (2011) Mammalian genomic imprinting. Cold Spring Harb Perspect Biol 3, a002592.
20.Kulis, M & Esteller, M (2010) DNA methylation and cancer. Adv Genet 70, 2756.
21.Sanchez-Mut, JV, Heyn, H, Vidal, E et al. (2016) Human DNA methylomes of neurodegenerative diseases show common epigenomic patterns. Transl Psychiatry 6, e718.
22.Richardson, B (2003) DNA methylation and autoimmune disease. Clin Immunol 109, 7279.
23.Merlo, A, Herman, JG, Mao, L et al. (1995) 5' CpG island methylation is associated with transcriptional silencing of the tumour suppressor p16/CDKN2/MTS1 in human cancers. Nat Med 1, 686692.
24.Gaudet, F, Hodgson, JG, Eden, A et al. (2003) Induction of tumors in mice by genomic hypomethylation. Science 300, 489492.
25.Rosty, C, Ueki, T, Argani, P et al. (2002) Overexpression of S100A4 in pancreatic ductal adenocarcinomas is associated with poor differentiation and DNA hypomethylation. Am J Pathol 160, 4550.
26.Christensen, BC, Kelsey, KT, Zheng, S et al. (2010) Breast Cancer DNA methylation profiles Are associated with tumor size and alcohol and folate intake. PLoS Genet 6, e1001043.
27.Piyathilake, CJ, Badiga, S, Borak, SG et al. (2017) A higher degree of expression of DNA methyl transferase 1 in cervical cancer is associated with poor survival outcome. Int J Womens Health 9, 413420.
28.Mizuno, S, Chijiwa, T, Okamura, T et al. (2001) Expression of DNA methyltransferases DNMT1, 3A, and 3B in normal hematopoiesis and in acute and chronic myelogenous leukemia. Blood 97, 11721179.
29.Mizuno, S-I, Chijiwa, T, Okamura, T et al. (2001) Expression of DNA methyltransferases DNMT1,3A, and 3B in normal hematopoiesis and in acute and chronic myelogenous leukemia. Blood 97, 11721179.
30.Garcia-Bellido, A & Santamaria, P (1972) Developmental analysis of the wing disc in the mutant engrailed of DROSOPHILA MELANOGASTER. Genetics 72, 87104.
31.Zec, N, Rowitch, DH, Bitgood, MJ et al. (1997) Expression of the homeobox-containing genes EN1 and EN2 in human fetal midgestational medulla and cerebellum. J Neuropathol Exp Neurol 56, 236242.
32.Wilson, SL, Kalinovsky, A, Orvis, GD et al. (2011) Spatially restricted and developmentally dynamic expression of engrailed genes in multiple cerebellar cell types. Cerebellum (London, England) 10, 356372.
33.Mayor, R, Casadomé, L, Azuara, D et al. (2009) Long-range epigenetic silencing at 2q14·2 affects most human colorectal cancers and may have application as a non-invasive biomarker of disease. Br J Cancer 100, 15341539.
34.Devaney, J, Stirzaker, C, Qu, W et al. (2011) Epigenetic deregulation across chromosome 2q14·2 differentiates normal from prostate cancer and provides a regional panel of novel DNA methylation cancer biomarkers. Cancer Epidemiol Biomarkers Prev 20, 148159.
35.Carrascosa, LG, Sina, AAI, Palanisamy, R et al. (2014) Molecular inversion probe-based SPR biosensing for specific, label-free and real-time detection of regional DNA methylation. Chem Commun 50, 35853588.
36.Bell, A, Bell, D, Weber, RS et al. (2011) CpG island methylation profiling in human salivary gland adenoid cystic carcinoma. Cancer 117, 28982909.
37.Frigola, J, Song, J, Stirzaker, C et al. (2006) Epigenetic remodeling in colorectal cancer results in coordinate gene suppression across an entire chromosome band. Nature Genetics 38, 540.
38.Dobbins, M, Decorby, K & Choi, BCK (2013) The association between obesity and cancer risk: a meta-analysis of observational studies from 1985 to 2011. ISRN Prev Med 2013, 16.
39.Zhang, P, Chu, T, Dedousis, N et al. (2017) DNA methylation alters transcriptional rates of differentially expressed genes and contributes to pathophysiology in mice fed a high fat diet. Mol Metab 6, 327339.
40.Vucetic, Z, Kimmel, J & Reyes, TM (2011) Chronic high-fat diet drives postnatal epigenetic regulation of μ-opioid receptor in the brain. Neuropsychopharmacology 36, 11991206.
41.Han, X, Stevens, J, Truesdale, KP et al. (2014) Body mass index at early adulthood, subsequent weight change, and cancer incidence and mortality. Int J Cancer 135, 29002909.
42.Fradin, D, Boëlle, P-Y, Belot, M-P et al. (2017) Genome-wide methylation analysis identifies specific epigenetic marks in severely obese children. Sci Rep 7, 46311.
43.Xu, X, Su, S, Barnes, VA et al. (2013) A genome-wide methylation study on obesity: differential variability and differential methylation. Epigenetics 8, 522533.
44.García-Escobar, E, Monastero, R, García-Serrano, S et al. (2017) Dietary fatty acids modulate adipocyte TNFa production via regulation of its DNA promoter methylation levels. J Nutr Biochem 47, Suppl. C, 106112.
45.Tobi, EW, Goeman, JJ, Monajemi, R et al. (2014) DNA methylation signatures link prenatal famine exposure to growth and metabolism. Nat Commun 5, 5592.
46.Barker, DJ (1995) Intrauterine programming of adult disease. Mol Med Today 1, 418423.
47.Bouchard, L, Thibault, S, Guay, SP et al. (2010) Leptin gene epigenetic adaptation to impaired glucose metabolism during pregnancy. Diab Care 33, 24362441.
48.Rzehak, P, Covic, M, Saffery, R et al. (2017) DNA-methylation and body composition in preschool children: epigenome-wide-analysis in the European childhood obesity project (CHOP)-study. Sci Rep 7, 14349.
49.Zhang, H & Tsao, R (2016) Dietary polyphenols, oxidative stress and antioxidant and anti-inflammatory effects. Curr Opin Food Sci 8, Suppl. C, 3342.
50.Mileo, AM & Miccadei, S (2016) Polyphenols as modulator of oxidative stress in cancer disease: new therapeutic strategies. Oxid Med Cell Longev 2016, 17.
51.Fini, L, Selgrad, M, Fogliano, V et al. (2007) Annurca apple polyphenols have potent demethylating activity and can reactivate silenced tumor suppressor genes in colorectal cancer cells. J Nutr 137, 26222628.
52.Crescenti, A, Solà, R, Valls, RM et al. (2013) Cocoa consumption alters the global DNA methylation of peripheral leukocytes in humans with cardiovascular disease risk factors: a randomized controlled trial. PLoS ONE 8, e65744.
53.Nandakumar, V, Vaid, M & Katiyar, SK (2011) (-)-Epigallocatechin-3-gallate reactivates silenced tumor suppressor genes, Cip1/p21 and p16INK4a, by reducing DNA methylation and increasing histones acetylation in human skin cancer cells. Carcinogenesis 32, 537544.
54.Crider, KS, Yang, TP, Berry, RJ et al. (2012) Folate and DNA methylation: a review of molecular mechanisms and the evidence for folate's role. Adv Nutr Int Rev J 3, 2138.
55.Pogribny, IP, Ross, SA, Wise, C et al. (2006) Irreversible global DNA hypomethylation as a key step in hepatocarcinogenesis induced by dietary methyl deficiency. Mutat Res Fundam Mol Mech Mutagen 593, 8087.
56.Jung, AY, Smulders, Y, Verhoef, P et al. (2011) No effect of folic acid supplementation on global DNA methylation in men and women with moderately elevated homocysteine. PLoS ONE 6, e24976.
57.Pufulete, M, Al-Ghnaniem, R, Khushal, A et al. (2005) Effect of folic acid supplementation on genomic DNA methylation in patients with colorectal adenoma. Gut 54, 648653.
58.Park, HJ, Bailey, LB, Shade, DC et al. (2017) Distinctions in gene-specific changes in DNA methylation in response to folic acid supplementation between women with normal weight and obesity. Obes Res Clin Pract 11, 665676.
59.Crider, KS, Quinlivan, EP, Berry, RJ et al. (2011) Genomic DNA methylation changes in response to folic acid supplementation in a population-based intervention study among women of reproductive age. PLoS ONE 6, e28144.
60.Kim, CH, Lee, EK, Choi, YJ et al. (2016) Short-term calorie restriction ameliorates genomewide, age-related alterations in DNA methylation. Aging Cell 15, 10741081.
61.Hahn, O, Grönke, S, Stubbs, TM et al. (2017) Dietary restriction protects from age-associated DNA methylation and induces epigenetic reprogramming of lipid metabolism. Genome Biol 18, 56.
62.Wang, T, Tsui, B, Kreisberg, JF et al. (2017) Epigenetic aging signatures in mice livers are slowed by dwarfism, calorie restriction and rapamycin treatment. Genome Biol 18, 57.
63.Stresemann, C & Lyko, F (2008) Modes of action of the DNA methyltransferase inhibitors azacytidine and decitabine. Int J Cancer 123, 813.
64.Almasri, J, Alkhateeb, HB, Damlaj, M et al. (2015) Comparative analysis of azacitidine and decitabine in myelodysplastic syndromes: a systematic review and network meta-analysis. Blood 126, 1692.
65.Lee, YG, Kim, I, Yoon, SS et al. (2013) Comparative analysis between azacitidine and decitabine for the treatment of myelodysplastic syndromes. Br J Haematol 161, 339347.
66.Xie, M, Jiang, Q & Xie, Y (2015) Comparison between decitabine and azacitidine for the treatment of myelodysplastic syndrome: a meta-analysis with 1392 participants. Clin Lymphoma Myeloma Leuk 15, 2228.
67.Jabbour, E, Short, NJ, Montalban-Bravo, G et al. (2017) Randomized phase 2 study of low-dose decitabine v. low-dose azacitidine in lower-risk MDS and MDS/MPN. Blood 130, 15141522.
68.Chik, F & Szyf, M (2011) Effects of specific DNMT gene depletion on cancer cell transformation and breast cancer cell invasion; toward selective DNMT inhibitors. Carcinogenesis 32, 224232.
69.Mc Auley, MT & Mooney, KM (2015) Computational systems biology for aging research. Interdiscip Top Gerontol 40, 3548.
70.Mc Auley, MT, Wilkinson, DJ, Jones, JJL et al. (2012) A whole-body mathematical model of cholesterol metabolism and its age-associated dysregulation. BMC Syst Biol 6, 130.
71.Mc Auley, MT, Choi, H, Mooney, K et al. (2015) Systems biology and synthetic biology: a new epoch for toxicology research. Adv Toxicol 2015, 14.
72.Mooney, KM, Morgan, AE & Mc Auley, MT (2016) Aging and computational systems biology. Wiley Interdiscip Rev: Syst Biol Med 8, 123139.
73.Mc Auley, MT, Guimera, AM, Hodgson, D et al. (2017) Modelling the molecular mechanisms of aging. Biosci Rep 37, BSR20160177.
74.Mc Auley, MT, Proctor, CJ, Corfe, BM et al. (2013) Nutrition research and the impact of computational systems biology. J Comput Sci Syst Biol 6, 271285.
75.Morgan, AE, Mooney, KM, Wilkinson, SJ et al. (2016) Mathematically modelling the dynamics of cholesterol metabolism and ageing. Biosystems 145, 1932.
76.Mc Auley, MT, Mooney, KM & Salcedo-Sora, JE (2016) Computational modelling folate metabolism and DNA methylation: implications for understanding health and ageing. Brief Bioinform 19, 303317.
77.Kilner, J, Corfe, BM, McAuley, MT et al. (2016) A deterministic oscillatory model of microtubule growth and shrinkage for differential actions of short chain fatty acids. Mol BioSyst 12, 93101.
78.Salcedo-Sora, JE & Mc Auley, MT (2016) A mathematical model of microbial folate biosynthesis and utilisation: implications for antifolate development. Mol BioSyst 12, 923933.
79.Mc Auley, MT & Mooney, KM (2015) Computationally modeling lipid metabolism and aging: a mini-review. Comput Struct Biotechnol J 13, 3846.
80.Morgan, AE, Mooney, KM, Wilkinson, SJ et al. (2016) Cholesterol metabolism: a review of how ageing disrupts the biological mechanisms responsible for its regulation. Ageing Res Rev 27, 108124.
81.Hossain, T, Mahmudunnabi, G, Masud, MK et al. (2017) Electrochemical biosensing strategies for DNA methylation analysis. Biosens Bioelectron 94, 6373.
82.Li, Y & Tollefsbol, TO (2011) DNA methylation detection: bisulfite genomic sequencing analysis. Methods Mol Biol (Clifton, NJ) 791, 1121.
83.Herman, JG, Graff, JR, Myohanen, S et al. (1996) Methylation-specific PCR: a novel PCR assay for methylation status of CpG islands. Proc Natl Acad Sci USA 93, 98219826.
84.Tost, J & Gut, IG (2007) DNA methylation analysis by pyrosequencing. Nat Protoc 2, 22652275.
85.Rauch, T & Pfeifer, GP (2005) Methylated-CpG island recovery assay: a new technique for the rapid detection of methylated-CpG islands in cancer. Lab Invest 85, 11721180.
86.Armstrong, KM, Bermingham, EN, Bassett, SA et al. (2011) Global DNA methylation measurement by HPLC using low amounts of DNA. Biotechnol J 6, 113117.
87.Lin, XC, Zhang, T, Liu, L et al. (2016) Mass spectrometry based ultrasensitive DNA methylation profiling using target fragmentation assay. Anal Chem 88, 10831087.
88.Schumacher, A, Kapranov, P, Kaminsky, Z et al. (2006) Microarray-based DNA methylation profiling: technology and applications. Nucleic Acids Res 34, 528542.
89.Sina, AAI, Howell, S, Carrascosa, LG et al. (2014) eMethylsorb: electrochemical quantification of DNA methylation at CpG resolution using DNA-gold affinity interactions. Chem Commun 50, 13153–6.
90.Hu, J & Zhang, CY (2012) Single base extension reaction-based surface enhanced Raman spectroscopy for DNA methylation assay. Biosens Bioelectron 31, 451457.
91.Kimura-Suda, H, Petrovykh, DY, Tarlov, MJ et al. (2003) Base-dependent competitive adsorption of single-stranded DNA on gold. J Am Chem Soc 125, 90149015.
92.Koo, KM, Sina, AA, Carrascosa, LG et al. (2014) eMethylsorb: rapid quantification of DNA methylation in cancer cells on screen-printed gold electrodes. Analyst 139, 61786184.
93.Thompson, G, Davies, T, Mc Auley, M et al. (2016) Electrochemical detection of DNA methylation and application to breast cancer screening. Oral Present Abstr Electrochem Sens https://www2.le.ac.uk/conference/previous/electrochem2016/programme/electrochemical-sensing-abstracts.
94.Moelans, CB, de Groot, JS, Pan, X et al. (2014) Clonal intratumor heterogeneity of promoter hypermethylation in breast cancer by MS-MLPA. Mod Pathol 27, 869874.
95.Quek, K, Li, J, Estecio, M et al. (2017) DNA methylation intratumor heterogeneity in localized lung adenocarcinomas. Oncotarget 8, 2199422002.
96.Varley, KE, Mutch, DG, Edmonston, TB et al. (2009) Intra-tumor heterogeneity of MLH1 promoter methylation revealed by deep single molecule bisulfite sequencing. Nucleic Acids Res 37, 46034612.
97.Litovkin, K, Van Eynde, A, Joniau, S et al. (2015) DNA methylation-guided prediction of clinical failure in high-risk prostate cancer. PLoS ONE 10, e0130651.
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