Successful completion of the Human Genome Project gave the hope for development of novel therapeutics, diagnostics for the welfare of humankind. Individual genetic studies and genome wide association studies revealed the genetic risk factors for various diseases which can be used in predetermination. This eventually led to the growth of pharmacogenomics that confers individual drug dosage adjustment preventing from adverse effects. However, it addresses only the hitches raised by the underlying genetic sequence but not external factors that influences the genotypic and phenotypic expression. Epigenetic research deals with these factors and studies the modifications caused along with their phenotype. These modifications are reversible which can be used as target for therapeutics, thus improving the treatment strategies of various diseases. In this review, we attempt to discuss the use of epigenetic modifications as drug targets and their mechanism of action.
Waddington CH. The epigenotype. Endeavour. 1942;1:18-20.
Reik W. Stability and flexibility of epigenetic gene regulation in mammalian development. Nature. 2007; 447: 425-32.
Glant TT, Mikecz K, Rauch TA. Epigenetics in the pathogenesis of rheumatoid arthritis. BMC Med. 2014;12:35-9.
Brown R, Curry E, Magnani L, Wilhelm-Benartzi CS, Borley J. Poised epigenetic states and acquired drug resistance in cancer. Nat Rev Cancer. 2014;14:747-53.
Ho S, Johnson A, Tarapore P, Janakiram V, Zhang X, Leung Y. Environmental epigenetics and its implication on disease risk and health outcomes. ILAR J. 2012;53:289-305.
Tompkins JD, Hall C, Chen VC, Li AX, Wu X, Hsu D, et al. Epigenetic stability, adaptability, and reversibility in human embryonic stem cells. Proc Natl Acad Sci U S A. 2012; 109:12544-9.
Egger G, Liang G, Aparicio A, Jones PA. Epigenetics in human disease and prospects for epigenetic therapy. Nature. 2004;429:457-63.
Villeneuve LM, Natarajan R. The role of epigenetics in the pathology of diabetic complications. Am J Physiol Renal Physiol. 2010;299:F14-F25.
Sharma S, Kelly TK, Jones PA. Epigenetics in cancer. Carcinogenesis. 2010;31:27-36.
Javierre BM. Changes in the pattern of DNA methylation associate with twin discordance in systemic lupus erythematosus. Genome Res. 2010;20:170-9.
Feng J, Fan G. The role of DNA methylation in the central nervous system and neuropsychiatric disorders. Int Rev Neurobiol. 2009;89:67-84.
Keppler BR, Archer TK. Chromatin-modifying enzymes as therapeutic targets - Part 1. Expert Opin Ther Targets. 2008; 12: 1301-12.
Urdinguio RG, Sanchez-Mut JV, Esteller M. Epigenetic mechanisms in neurological diseases: genes, syndromes, and therapies. Lancet Neurol. 2009;8:1056-72.
Adcock IM, Ito K, Barnes PJ. Histone deacetylation: an important mechanism in inflammatory lung diseases. COPD. 2005;2:445-55.
Jones PA, Baylin SB. The epigenomics of cancer. Cell. 2007;128:683-92.
Berdasco M, Ropero S, Setien F, Fraga MF, Lapunzina P, et al. Epigenetic inactivation of the Sotos overgrowth syndrome gene histone methyltransferase NSD1 in human neuroblastoma and glioma. Proc Natl Acad Sci USA. 2009;106:21830-5.
Rana TM. Illuminating the silence: understanding the structure and function of small RNAs. Nat Rev Mol Cell Biol. 2007;8: 23-36.
Varambally S, Cao Q, Mani RS, Shankar S, Wang X, et al. Genomic loss of microRNA-101 leads to overexpression of histone methyltransferase EZH2 in cancer. Science. 2008;322:1695-9.
Ng EK, Tsang WP, Ng SS, Jin HC, Yu J, et al. MicroRNA-143 targets DNA methyltransferases 3A in colorectal cancer. Br J Cancer. 2009;101:699-706.
Fabbri M, Garzon R, Cimmino A, Liu Z, Zanesi N, et al. MicroRNA-29 family reverts aberrant methylation in lung cancer by targeting DNA methyltransferases 3A and 3B. Proc Natl Acad Sci USA. 2007;104:15805-10.
Calin GA, Croce CM. MicroRNA signatures in human cancers. Nat Rev Cancer. 2006;6: 857.66.
Yanaihara N, Caplen N, Bowman E, Seike M, Kumamoto K, et al. Unique microRNA molecular profiles in lung cancer diagnosis and prognosis. Cancer Cell, 2006;9: 189.98.
Karolina DS, Armugam A, Tavintharan S, Wong MTK, Lim SC, et al. MicroRNA 144 impairs insulin signaling by inhibiting the expression of insulin receptor substrate 1 in type 2 diabetes mellitus. PLoS One. 2011; 6: e22839.
Rong Y, Bao W, Shan Z, Liu J, Yu X, et al. Increased microRNA-146a levels in plasma of patients with newly diagnosed type 2 diabetes mellitus. PLoS One. 2013; 8: e73272.
Slusarz A, Pulakat L. The two faces of miR-29. J Cardiovasc Med (Hagerstown). 2015; 16: 480.90.
Wang TT, Chen YJ, Sun LL, Zhang SJ, Zhou ZY, et al. Affection of single-nucleotide polymorphisms in miR-27a, miR-124a, and miR-146a on susceptibility to type 2 diabetes mellitus in Chinese Han people. Chin Med J (Engl) 2015; 128: 533.9.
Saab YB, Zeenny R, Ramadan WH. Optimizing clopidogrel dose response: a new clinical algorithm comprising CYP2C19 pharmacogenetics and drug interactions. Ther Clin Risk Manag. 2015;11:1421-7.
Ingelman-Sundberg M, Gomez A. The past, present and future of pharmacoepigenomics. Pharmacogenomics. 2010;11:625-7.
Anttila S, Hakkola J, Tuominen P. Methylation of cytochrome P4501A1 promoter in the lung is associated with tobacco smoking. Cancer Res. 2003;63:8623.8.
Nakajima M, Iwanari M, Yokoi T. Effects of histone deacetylation and DNA methylation on the constitutive and TCDD-inducible expressions of the human CYP1 family in MCF-7 and HeLa cells. Toxicol Lett. 2003;144:247-56.
Ibanez de Caceres I, Cortes-Sempere M, Moratilla C, Machado-Pinilla R, et al. IGFBP-3 hypermethylation-derived deficiency mediates cisplatin resistance in non-smallcell lung cancer. Oncogene. 2010;29:1681.90.
Martens JW, Margossian AL, Schmitt M, Foekens J, Harbeck N. DNA methylation as a biomarker in breast cancer. Future Oncol. 2009;5:1245.56.
Jarmalaite S, Andrekute R, Scesnaite A, Suziedelis K, Husgafvel-Pursiainen K, et al. Promoter hypermethylation in tumour suppressor genes and response to interleukin-2 treatment in bladder cancer: a pilot study. J Cancer Res Clin Oncol. 2010;136:847-54.
Claes B, Buysschaert I, Lambrechts D. Pharmaco-epigenomics: discovering therapeutic approaches and biomarkers for cancer therapy. Heredity. 2010;105:152.60.
Lapeyre JN, Becker FF. 5-Methylcytosine content of nuclear DNA during chemical hepatocarcinogenesis and in carcinomas which result. Biochem Biophys Res Commun. 1979;87:698.705.
Herman JG, Baylin SB. Gene silencing in cancer in association with promoter hypermethylation. N Engl J Med. 2003;349:2042.54.
Egger G, Liang G, Aparicio A, Jones PA. Epigenetics in human disease and prospects for epigenetic therapy. Nature. 2004;429:457.63.
Issa JP, Kantarjian HM, Kirkpatrick P. Azacitidine. Nat Rev Drug Discov. 2005;4:275. 6.
Kantarjian H, Issa JP, Rosenfeld CS. Decitabine improves patient outcomes in myelodysplastic syndromes: results of a phase III randomized study. Cancer. 2006;106:1794- 803.
Fenaux P, Mufti GJ, Hellstrom-Lindberg E, Santini V, Finelli C, et al. Efficacy of azacitidine compared with that of conventional care regimens in the treatment of higher-risk myelodysplastic syndromes: a randomised, open-label, phase III study. Lancet Oncol. 2009;10:223.32.
Silverman LR, McKenzie DR, Peterson BL, Holland JF, Backstrom JT, et al. Further analysis of trials with azacitidine in patients with myelodysplastic syndrome: studies 8421, 8921, and 9221 by the Cancer and Leukemia Group B. J Clin Oncol. 2006;24:3895.903.
Kantarjian HM, O'Brien S, Shan J, Aribi A, Garcia-Manero G, et al. Update of the decitabine experience in higher risk myelodysplastic syndrome and analysis of prognostic factors associated with outcome. Cancer. 2007;109:265.73.
Dayeh T, Volkov P, Salo S, Hall E, Nilsson E, et al. Genome-wide DNA methylation analysis of human pancreatic islets from Type 2 diabetic and non-diabetic donors identifies candidate genes that influence insulin secretion. PLoS Genet. 2014;10:e1004160.
Dhas BB, Antony HA, Bhat V, Newton B, Parija SC. Global DNA methylation in neonatal sepsis. Indian J Pediatr. 2015;82:340-4.
Dhas BB, Antony HA, Bhat V, Parija SC. Functional annotation of protocadherin beta genes hypermethylation and their significance in neonatal sepsis. Int J Cur Res Rev. 2015;7:23-7.
Dhas BB, Antony HA, Bhat V, Kalaivani S, Parija SC. Comparison of genomic DNA methylation pattern among septic and non-septic newborns - An epigenome wide association study. Genomics Data. 2015;3: 36.40.
Jha AK, Nikbakht M, Parashar G, Shrivastava A, Capalash N, et al. Reversal of hypermethylation and reactivation of the RARβ2 gene by natural compounds in cervical cancer cell lines. Folia Biol (Praha). 2010;56:195-200.
Miwa M, Tsuboi M, Noguchi Y, Enokishima A, Nabeshima T, et al. Effects of betaine on lipopolysaccharide-induced memory impairment in mice and the involvement of GABA transporter 2. J Neuroinflammation. 2011; 8:153-65.
Gore SD, Weng LJ, Zhai S, Figg WD, Donehower RC, et al. Impact of the putative differentiating agent sodium phenylbutyrate on myelodysplastic syndromes and acute myeloid leukemia. Clin Cancer Res. 2001;7:2330.9.
Garcia-Manero G, Yang H, Bueso-Ramos C, Ferrajoli A, Cortes J, et al. Phase 1 study of the histone deacetylase inhibitor vorinostat (suberoylanilide hydroxamic acid [SAHA]) in patients with advanced leukemias and myelodysplastic syndromes. Blood. 2008;111: 1060.6.
Phiel CJ, Zhang F, Huang EY, Guenther MG, Lazar MA, Klein PS. Histone deacetylase is a direct target of valproic acid, a potent anticonvulsant, mood stabilizer, and teratogen. J Biol Chem. 2001; 276:36734-41.
Gottlicher M, Minucci S, Zhu P, Kramer OH, Schimpf A, et al. Valproic acid defines a novel class of HDAC inhibitors inducing differentiation of transformed cells. EMBO J. 2001; 20:6969-78.
Kramer OH, Zhu P, Ostendorff HP, Golebiewski M, Tiefenbach J, et al. The histone deacetylase inhibitor valproic acid selectively induces proteasomal degradation of HDAC2. EMBO J. 2003; 22:3411-20.
Ricobaraza A, Cuadrado-Tejedor M, Perez-Mediavilla A, Frechilla D, Del Rio J, et al. Phenylbutyrate ameliorates cognitive deficit and reduces tau pathology in an Alzheimer's disease mouse model. Neuropsychopharmacology. 2009;34:1721-32.
Albani D, Polito L, Forloni G. Sirtuins as novel targets for Alzheimer's disease and other neurodegenerative disorders: experimental and genetic evidence. J Alzheimers Dis. 2010; 19:11-26.
Min SW, Cho SH, Zhou Y, Schroeder S, Haroutunian V, et al. Acetylation of tau inhibits its degradation and contributes to tauopathy. Neuron. 2010; 67:953-66.
Balasubramanyam K, Varier RA, Altaf M, Swaminathan V, Siddappa NB, et al. Curcumin, a novel p300/CREB-binding protein-specific inhibitor of acetyltransferase, represses the acetylation of histone/nonhistone proteins and histone acetyltransferase-dependent chromatin transcription. J Biol Chem. 2004; 279:51163-71.
Tucker S, Ahl M, Cho HH, Bandyopadhyay S, Cuny GD, Bush AI, et al. RNA therapeutics directed to the non-coding regions of APP mRNA, in vivo anti-amyloid efficacy of paroxetine, erythromycin, and N-acetyl cysteine. Curr Alzheimer Res. 2006; 3:221-7.
