The Emerging Role of Epigenetics

  • Lu Qian Wang
  • Kailash Singh
  • Aung Moe Zaw
  • Billy Kwok Chong ChowEmail author
Part of the Translational Bioinformatics book series (TRBIO, volume 16)


Epigenetics is one of the most rapidly expanding fields in biology over the past decades. Epigenetic mechanisms, including DNA methylation, histone modifications, and RNA-associated editing, lead to the heritable silencing/activation of genes without changes in DNA sequence. The critical role of epigenetic modifications has been demonstrated in normal and disease development in humans. With the advent of next-generation sequencing, the technological breakthrough makes it possible to unveil the genome-wide mapping of epigenetic changes. Here, we give a comprehensive overview of epigenetic mechanisms and focus on the recent progress of epigenetic modifications involved in the pathogenesis or progression of human diseases, in particular, cardiovascular diseases and cancers. In addition, some current epigenetic therapies including the inhibitors of DNA methyltransferases and histone deacetylases that have shown promising therapeutic effects will be also discussed.


Epigenetics DNA methylation Histone modification miRNAs and lncRNAs 


3′ UTR

3′ untranslated region




Coronary artery diseases


Chromatin immunoprecipitation


Cardiovascular diseases


Dilated cardiomyopathies


DNA methyltransferases


Endothelial nitric oxide synthase


Histone acetyltransferases


Histone deacetylases


Heart failure


Inducible nitric oxide synthase


Long noncoding RNAs


Methyl-CpG-binding proteins




Next-generation sequencing


Nitric oxide


Pulmonary arterial hypertension


Smooth muscle cells


Tumor suppressor genes



This work was supported by Hong Kong Research Grants Council – General Research Fund (HKU 17127215; project title: Molecular Mechanisms Underlying the Progressive Development of Pulmonary Arterial Hypertension in Secretin Knockout Mice; PI: Professor BKC Chow, School of Biological Sciences; 1,100,302 HKD, ongoing).


  1. Akat KM, et al. Comparative RNA-sequencing analysis of myocardial and circulating small RNAs in human heart failure and their utility as biomarkers. Proc Natl Acad Sci. 2014;111(30):11151–6.PubMedCrossRefGoogle Scholar
  2. Alegría-Torres JA, et al. Epigenetics and lifestyle. Epigenomics. 2011;3:267–77.PubMedPubMedCentralCrossRefGoogle Scholar
  3. Allegrucci C, et al. Restriction landmark genome scanning identifies culture-induced DNA methylation instability in the human embryonic stem cell epigenome. Hum Mol Genet. 2007;16(10):1253–68.PubMedCrossRefGoogle Scholar
  4. Amato RJ. Inhibition of DNA methylation by antisense oligonucleotide MG98 as cancer therapy. Clin Genitourin Cancer. 2007;5(7):422–6.PubMedCrossRefGoogle Scholar
  5. Ambrose JA, et al. Angiographic progression of coronary artery disease and the development of myocardial infarction. J Am Coll Cardiol. 1988;12(1):56–62.PubMedCrossRefGoogle Scholar
  6. Antequera F, Bird A. CpG islands. DNA methylation. New York: Springer; 1993. p. 169–85.CrossRefGoogle Scholar
  7. Baccarelli A, Ghosh S. Environmental exposures, epigenetics and cardiovascular disease. Curr Opin Clin Nutr Metab Care. 2012;15(4):323.PubMedPubMedCentralCrossRefGoogle Scholar
  8. Baccarelli A, et al. Ischemic heart disease and stroke in relation to blood DNA methylation. Epidimiology. 2010;21(6):819.CrossRefGoogle Scholar
  9. Bachman KE, et al. Dnmt3a and Dnmt3b are transcriptional repressors that exhibit unique localization properties to heterochromatin. J Biol Chem. 2001;276(34):32282–7.PubMedCrossRefGoogle Scholar
  10. Ballestar E, Esteller M. Methyl-CpG-binding proteins in cancer: blaming the DNA methylation messenger. Biochem Cell Biol. 2005;83(3):374–84.PubMedCrossRefGoogle Scholar
  11. Bandyopadhyay K, et al. Spermidinyl-CoA-based HAT inhibitors block DNA repair and provide cancer-specific chemo-and radiosensitization. Cell Cycle. 2009;8(17):2779–88.PubMedPubMedCentralCrossRefGoogle Scholar
  12. Bang C, et al. Cardiac fibroblast–derived microRNA passenger strand-enriched exosomes mediate cardiomyocyte hypertrophy. J Clin Invest. 2014;124(5):2136.PubMedPubMedCentralCrossRefGoogle Scholar
  13. Barski A, et al. High-resolution profiling of histone methylations in the human genome. Cell. 2007;129(4):823–37.CrossRefGoogle Scholar
  14. Bartel D. MicroRNAs: genomics, biogenesis, mechanism, and function. Cell. 2004;116(2):281–97.CrossRefGoogle Scholar
  15. Bartel DP. MicroRNAs: target recognition and regulatory functions. Cell. 2009;136(2):215–33.PubMedPubMedCentralCrossRefGoogle Scholar
  16. Batista PJ, Chang HY. Long noncoding RNAs: cellular address codes in development and disease. Cell. 2013;152(6):1298–307.PubMedPubMedCentralCrossRefGoogle Scholar
  17. Belinsky SA, et al. Inhibition of DNA methylation and histone deacetylation prevents murine lung cancer. Cancer Res. 2003;63(21):7089–93.PubMedGoogle Scholar
  18. Bellet MM, Sassone-Corsi P. Mammalian circadian clock and metabolism–the epigenetic link. J Cell Sci. 2010;123(22):3837–48.PubMedPubMedCentralCrossRefGoogle Scholar
  19. Berger SL. The complex language of chromatin regulation during transcription. Nature. 2007;447(7143):407–12.PubMedCrossRefGoogle Scholar
  20. Bird AP. CpG-rich islands and the function of DNA methylation. Nature. 1986;321(6067):209–13.PubMedCrossRefGoogle Scholar
  21. Bird A. DNA methylation patterns and epigenetic memory. Genes Dev. 2002;16(1):6–21.PubMedCrossRefGoogle Scholar
  22. Blander G, Guarente L. The Sir2 family of protein deacetylases. Annu Rev Biochem. 2004;73(1):417–35.CrossRefGoogle Scholar
  23. Bogdarina I, et al. Epigenetic modification of the renin-angiotensin system in the fetal programming of hypertension. Circ Res. 2007;100(4):520–6.PubMedPubMedCentralCrossRefGoogle Scholar
  24. Boon RA, et al. MicroRNA-34a regulates cardiac ageing and function. Nature. 2013;495(7439):107–10.PubMedCrossRefGoogle Scholar
  25. Bowers EM, et al. Virtual ligand screening of the p300/CBP histone acetyltransferase: identification of a selective small molecule inhibitor. Chem Biol. 2010;17(5):471–82.PubMedPubMedCentralCrossRefGoogle Scholar
  26. Branco MR, et al. Safeguarding parental identity: Dnmt1 maintains imprints during epigenetic reprogramming in early embryogenesis. Genes Dev. 2008;22(12):1567–71.PubMedPubMedCentralCrossRefGoogle Scholar
  27. Breton CV, et al. Prenatal tobacco smoke exposure affects global and gene-specific DNA methylation. Am J Respir Crit Care Med. 2009;180(5):462–7.PubMedPubMedCentralCrossRefGoogle Scholar
  28. Brown R, Strathdee G. Epigenomics and epigenetic therapy of cancer. Trends Mol Med. 2002;8(4):S43–8.PubMedCrossRefGoogle Scholar
  29. Brown CE, et al. The many HATs of transcription coactivators. Trends Biochem Sci. 2000;25(1):15–9.PubMedCrossRefGoogle Scholar
  30. Brunner AL, et al. Transcriptional profiling of long non-coding RNAs and novel transcribed regions across a diverse panel of archived human cancers. Genome Biol. 2012;13(8):R75.PubMedPubMedCentralCrossRefGoogle Scholar
  31. Byun HM, et al. Effects of air pollution and blood mitochondrial DNA methylation on markers of heart rate variability. J Am Heart Assoc. 2016;5(4):e003218.PubMedPubMedCentralCrossRefGoogle Scholar
  32. Calin GA, Croce CM. MicroRNA signatures in human cancers. Nat Rev Cancer. 2006;6:857–66.CrossRefGoogle Scholar
  33. Cao D, et al. Modulation of smooth muscle gene expression by association of histone acetyltransferases and deacetylases with myocardin. Mol Cell Biol. 2005;25(1):364–76.PubMedPubMedCentralCrossRefGoogle Scholar
  34. Cao DJ, et al. Histone deacetylase (HDAC) inhibitors attenuate cardiac hypertrophy by suppressing autophagy. Proc Natl Acad Sci. 2011;108(10):4123–8.PubMedCrossRefGoogle Scholar
  35. Chan GC, et al. Epigenetic basis for the transcriptional hyporesponsiveness of the human inducible nitric oxide synthase gene in vascular endothelial cells. J Immunol. 2005;175(6):3846–61.PubMedCrossRefGoogle Scholar
  36. Chen J, et al. Highly sensitive and specific microRNA expression profiling using BeadArray technology. Nucleic Acids Res. 2008;36(14):e87.PubMedPubMedCentralCrossRefGoogle Scholar
  37. Chen SS, et al. Elevated plasma prostaglandins and acetylated histone in monocytes in type 1 diabetes patients. Diabet Med. 2009a;26(2):182–6.PubMedCrossRefGoogle Scholar
  38. Chen Y, et al. Reproducibility of quantitative RT-PCR array in miRNA expression profiling and comparison with microarray analysis. BMC Genomics. 2009b;10(1):407.PubMedPubMedCentralCrossRefGoogle Scholar
  39. Chen J, et al. Leukaemogenesis: more than mutant genes. Nat Rev Cancer. 2010;10(1):23–36.PubMedPubMedCentralCrossRefGoogle Scholar
  40. Cheng JC, et al. Inhibition of DNA methylation and reactivation of silenced genes by zebularine. J Natl Cancer Inst. 2003;95(5):399–409.PubMedCrossRefGoogle Scholar
  41. Cheng JC, et al. Preferential response of cancer cells to zebularine. Cancer Cell. 2004;6(2):151–8.PubMedCrossRefGoogle Scholar
  42. Cheung WL, et al. Acetylation and chromosomal functions. Curr Opin Cell Biol. 2000;12(3):326–33.PubMedCrossRefGoogle Scholar
  43. Chim CS, et al. SOCS1 and SHP1 hypermethylation in multiple myeloma: implications for epigenetic activation of the Jak/STAT pathway. Blood. 2004;103(12):4630–5.PubMedCrossRefGoogle Scholar
  44. Chim SS, et al. Detection and characterization of placental microRNAs in maternal plasma. Clin Chem. 2008;54(3):482–90.PubMedPubMedCentralCrossRefGoogle Scholar
  45. Choi J-H, et al. Trichostatin a exacerbates atherosclerosis in low density lipoprotein receptor–deficient mice. Arterioscler Thromb Vasc Biol. 2005;25(11):2404–9.PubMedCrossRefGoogle Scholar
  46. Christman JK. 5-Azacytidine and 5-aza-2′-deoxycytidine as inhibitors of DNA methylation: mechanistic studies and their implications for cancer therapy. Oncogene. 2002;21(35):5483–95.PubMedCrossRefGoogle Scholar
  47. Chuang JC, et al. Comparison of biological effects of non-nucleoside DNA methylation inhibitors versus 5-aza-2′-deoxycytidine. Mol Cancer Ther. 2005;4(10):1515–20.PubMedCrossRefGoogle Scholar
  48. Closs EI, et al. Interference of L-arginine analogues with L-arginine transport mediated by the y+ carrier hCAT-2B. Nitric Oxide. 1997;1(1):65–73.PubMedCrossRefGoogle Scholar
  49. Cokus SJ, et al. Shotgun bisulphite sequencing of the Arabidopsis genome reveals DNA methylation patterning. Nature. 2008;452(7184):215–9.PubMedPubMedCentralCrossRefGoogle Scholar
  50. Costello JF, et al. Aberrant CpG-island methylation has non-random and tumour-type–specific patterns. Nat Genet. 2000;24(2):132.PubMedCrossRefGoogle Scholar
  51. Cross SH, et al. Purification of CpG islands using a methylated DNA binding column. Nat Genet. 1994;6(3):236–44.CrossRefGoogle Scholar
  52. Dahl C, Guldberg P. DNA methylation analysis techniques. Biogerontology. 2003;4(4):233–50.PubMedCrossRefGoogle Scholar
  53. Dai D-F, et al. Cardiac aging: from molecular mechanisms to significance in human health and disease. Antioxid Redox Signal. 2012;16(12):1492–526.PubMedPubMedCentralCrossRefGoogle Scholar
  54. Daujat S, et al. Crosstalk between CARM1 methylation and CBP acetylation on histone H3. Curr Biol. 2002;12(24):2090–7.PubMedCrossRefGoogle Scholar
  55. Davey JW, et al. Genome-wide genetic marker discovery and genotyping using next-generation sequencing. Nat Rev Genet. 2011;12(7):499–510.CrossRefGoogle Scholar
  56. de Lucia C, et al. microRNA in cardiovascular aging and age-related cardiovascular diseases. Front Med. 2017;4(74):74.CrossRefGoogle Scholar
  57. Dekker FJ, Haisma HJ. Histone acetyl transferases as emerging drug targets. Drug Discov Today. 2009;14(19):942–8.PubMedCrossRefGoogle Scholar
  58. Dekker RJ, et al. KLF2 provokes a gene expression pattern that establishes functional quiescent differentiation of the endothelium. Blood. 2006;107(11):4354–63.PubMedCrossRefGoogle Scholar
  59. Denli AM, et al. Processing of primary microRNAs by the microprocessor complex. Nature. 2004;432(7014):231–5.CrossRefGoogle Scholar
  60. Dhordain P, et al. The LAZ3 (BCL-6) oncoprotein recruits a SMRT/mSIN3A/histone deacetylase containing complex to mediate transcriptional repression. Nucleic Acids Res. 1998;26(20):4645–51.PubMedPubMedCentralCrossRefGoogle Scholar
  61. Djebali S, et al. Landscape of transcription in human cells. Nature. 2012;489(7414):101–8.PubMedPubMedCentralCrossRefGoogle Scholar
  62. Dong C, et al. DNA methylation and atherosclerosis. J Nutr. 2002;132(8):2406S–9S.PubMedCrossRefGoogle Scholar
  63. Doran AC, et al. Role of smooth muscle cells in the initiation and early progression of atherosclerosis. Arterioscler Thromb Vasc Biol. 2008;28(5):812–9.PubMedPubMedCentralCrossRefGoogle Scholar
  64. Du Y, et al. Air particulate matter and cardiovascular disease: the epidemiological, biomedical and clinical evidence. J Thorac Dis. 2016;8(1):E8.PubMedPubMedCentralGoogle Scholar
  65. Dückelmann C, et al. Asymmetric dimethylarginine enhances cardiovascular risk prediction in patients with chronic heart failure. Arterioscler Thromb Vasc Biol. 2007;27(9):2037–42.PubMedCrossRefGoogle Scholar
  66. Dupont J-M, et al. De novo quantitative bisulfite sequencing using the pyrosequencing technology. Anal Biochem. 2004;333(1):119–27.PubMedCrossRefGoogle Scholar
  67. Duvic M, et al. Phase 2 trial of oral vorinostat (suberoylanilide hydroxamic acid, SAHA) for refractory cutaneous T-cell lymphoma (CTCL). Blood. 2007;109(1):31–9.PubMedPubMedCentralCrossRefGoogle Scholar
  68. Egger G, et al. Epigenetics in human disease and prospects for epigenetic therapy. Nature. 2004;429(6990):457–63.PubMedCrossRefGoogle Scholar
  69. Elia L, et al. Reciprocal regulation of microRNA-1 and insulin-like growth factor-1 signal transduction cascade in cardiac and skeletal muscle in physiological and pathological conditions. Circulation. 2009;120(23):2377–85.PubMedPubMedCentralCrossRefGoogle Scholar
  70. El-Maarri O, et al. Gender specific differences in levels of DNA methylation at selected loci from human total blood: a tendency toward higher methylation levels in males. Hum Genet. 2007;122(5):505–14.PubMedCrossRefGoogle Scholar
  71. Esteller M. Epigenetic gene silencing in cancer: the DNA hypermethylome. Hum Mol Genet. 2007;16(R1):R50–9.PubMedCrossRefGoogle Scholar
  72. Esteller M. Non-coding RNAs in human disease. Nat Rev Genet. 2011;12(12):861–74.PubMedPubMedCentralCrossRefGoogle Scholar
  73. Everson CA, et al. Antioxidant defense responses to sleep loss and sleep recovery. Am J Phys Regul Integr Comp Phys. 2005;288(2):R374–83.Google Scholar
  74. Feinberg AP, Vogelstein B. Hypomethylation distinguishes genes of some human cancers from their normal counterparts. Nature. 1983;301(5895):89–92.PubMedCrossRefGoogle Scholar
  75. Fenaux P, 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(3):223–32.PubMedPubMedCentralCrossRefGoogle Scholar
  76. Fetahu IS, et al. Vitamin D and the epigenome. Front Physiol. 2014;5:164.PubMedPubMedCentralCrossRefGoogle Scholar
  77. Fischer SG, Lerman LS. Length-independent separation of DNA restriction fragments in two-dimensional gel electrophoresis. Cell. 1979;16(1):191–200.PubMedCrossRefGoogle Scholar
  78. Fish JE, et al. The expression of endothelial nitric-oxide synthase is controlled by a cell-specific histone code. J Biol Chem. 2005;280(26):24824–38.PubMedCrossRefGoogle Scholar
  79. Fraga MF, Esteller M. DNA methylation: a profile of methods and applications. BioTechniques. 2002;33(3):632–49.PubMedCrossRefGoogle Scholar
  80. Friedman JM, Jones PA. MicroRNAs: critical mediators of differentiation, development and disease. Swiss Med Wkly. 2009;139(33–34):466–72.PubMedPubMedCentralGoogle Scholar
  81. Friedman RC, et al. Most mammalian mRNAs are conserved targets of microRNAs. Genome Res. 2009;19(1):92–105.PubMedPubMedCentralCrossRefGoogle Scholar
  82. Frommer M, et al. A genomic sequencing protocol that yields a positive display of 5-methylcytosine residues in individual DNA strands. Proc Natl Acad Sci. 1992;89(5):1827–31.PubMedCrossRefGoogle Scholar
  83. Gallo A, et al. The majority of microRNAs detectable in serum and saliva is concentrated in exosomes. PLoS One. 2012;7(3):e30679.PubMedPubMedCentralCrossRefGoogle Scholar
  84. Geng T, et al. Histone modification analysis by chromatin immunoprecipitation from a low number of cells on a microfluidic platform. Lab Chip. 2011;11(17):2842–8.PubMedCrossRefGoogle Scholar
  85. Gluckman PD, et al. Effect of in utero and early-life conditions on adult health and disease. N Engl J Med. 2008;359(1):61–73.PubMedPubMedCentralCrossRefGoogle Scholar
  86. Gluckman PD, et al. Epigenetic mechanisms that underpin metabolic and cardiovascular diseases. Nat Rev Endocrinol. 2009;5(7):401–8.PubMedCrossRefGoogle Scholar
  87. Goldberg AD, et al. Epigenetics: a landscape takes shape. Cell. 2007;128(4):635–8.PubMedCrossRefGoogle Scholar
  88. Goll MG, Bestor TH. Eukaryotic cytosine methyltransferases. Annu Rev Biochem. 2005;74:481–514.PubMedCrossRefGoogle Scholar
  89. Gottesfeld JM, Forbes DJ. Mitotic repression of the transcriptional machinery. Trends Biochem Sci. 1997;22(6):197–202.PubMedCrossRefGoogle Scholar
  90. Granger A, et al. Histone deacetylase inhibition reduces myocardial ischemia-reperfusion injury in mice. FASEB J. 2008;22(10):3549–60.PubMedPubMedCentralCrossRefGoogle Scholar
  91. Gregory RI, et al. The microprocessor complex mediates the genesis of microRNAs. Nature. 2004;432(7014):235–40.CrossRefGoogle Scholar
  92. Grewal SI, Moazed D. Heterochromatin and epigenetic control of gene expression. Science. 2003;301(5634):798–802.PubMedCrossRefGoogle Scholar
  93. Griffith J, Mahler H. DNA ticketing theory of memory. Nature. 1969;223:580–2.PubMedCrossRefGoogle Scholar
  94. Grunstein M. Histone acetylation in chromatin structure and transcription. Nature. 1997;389(6649):349–52.PubMedCrossRefGoogle Scholar
  95. Gupta A, et al. Hypomethylation of the synuclein γ gene CpG island promotes its aberrant expression in breast carcinoma and ovarian carcinoma. Cancer Res. 2003;63(3):664–73.PubMedGoogle Scholar
  96. Gusterson R, et al. The transcriptional co-activators CBP and p300 are activated via phenylephrine through the p42/p44 MAPK cascade. J Biol Chem. 2002;277(4):2517–24.PubMedCrossRefGoogle Scholar
  97. Gusterson RJ, et al. The transcriptional co-activators CREB-binding protein (CBP) and p300 play a critical role in cardiac hypertrophy that is dependent on their histone acetyltransferase activity. J Biol Chem. 2003;278(9):6838–47.PubMedCrossRefGoogle Scholar
  98. Haas J, et al. Alterations in cardiac DNA methylation in human dilated cardiomyopathy. EMBO Mol Med. 2013;5(3):413–29.PubMedPubMedCentralCrossRefGoogle Scholar
  99. Han J, et al. The Drosha-DGCR8 complex in primary microRNA processing. Genes Dev. 2004;18(24):3016–27.PubMedPubMedCentralCrossRefGoogle Scholar
  100. Hatada I, et al. A genomic scanning method for higher organisms using restriction sites as landmarks. Proc Natl Acad Sci. 1991;88(21):9523–7.PubMedCrossRefGoogle Scholar
  101. Hayatsu H. Discovery of bisulfite-mediated cytosine conversion to uracil, the key reaction for DNA methylation analysis – a personal account. Proc Jpn Acad Ser B. 2008;84(8):321–30.CrossRefGoogle Scholar
  102. Heidenreich PA, et al. Forecasting the future of cardiovascular disease in the United States. Policy Statement Am Heart Assoc. 2011;123(8):933–44.Google Scholar
  103. Heijmans BT, et al. Persistent epigenetic differences associated with prenatal exposure to famine in humans. Proc Natl Acad Sci U S A. 2008;105(44):17046–9.PubMedPubMedCentralCrossRefGoogle Scholar
  104. Hergenreider E, et al. Atheroprotective communication between endothelial cells and smooth muscle cells through miRNAs. Nat Cell Biol. 2012;14(3):249–56.PubMedCrossRefGoogle Scholar
  105. Herman JG, Baylin SB. Gene silencing in cancer in association with promoter hypermethylation. N Engl J Med. 2003;349(21):2042–54.PubMedCrossRefGoogle Scholar
  106. Herman J, et al. Methylation-specific PCR: a novel PCR assay for methylation status of CpG islands. Proc Natl Acad Sci U S A. 1996;93:9821–6.PubMedPubMedCentralCrossRefGoogle Scholar
  107. Hiltunen MO, Ylä-Herttuala S. DNA methylation, smooth muscle cells, and atherogenesis. Arterioscler Thromb Vasc Biol. 2003;23(10):1750–3.PubMedCrossRefGoogle Scholar
  108. Hiltunen MO, et al. DNA hypomethylation and methyltransferase expression in atherosclerotic lesions. Vasc Med. 2002;7(1):5–11.PubMedCrossRefGoogle Scholar
  109. Hodawadekar S, Marmorstein R. Chemistry of acetyl transfer by histone modifying enzymes: structure, mechanism and implications for effector design. Oncogene. 2007;26(37):5528–40.PubMedCrossRefGoogle Scholar
  110. Holliday R, Pugh JE. DNA modification mechanisms and gene activity during development. Science. 1975;187(4173):226–32.PubMedCrossRefGoogle Scholar
  111. Howard G, et al. Activation and transposition of endogenous retroviral elements in hypomethylation induced tumors in mice. Oncogene. 2008;27(3):404–8.PubMedCrossRefGoogle Scholar
  112. Hunter MP, et al. Detection of microRNA expression in human peripheral blood microvesicles. PLoS One. 2008;3(11):e3694.PubMedPubMedCentralCrossRefGoogle Scholar
  113. Huynh KD, Lee JT. X-chromosome inactivation: a hypothesis linking ontogeny and phylogeny. Nat Rev Genet. 2005;6(5):410–8.PubMedCrossRefGoogle Scholar
  114. Illingworth R, et al. A novel CpG island set identifies tissue-specific methylation at developmental gene loci. PLoS Biol. 2008;6(1):e22.PubMedPubMedCentralCrossRefGoogle Scholar
  115. Issa J-PJ, et al. Phase 1 study of low-dose prolonged exposure schedules of the hypomethylating agent 5-aza-2′-deoxycytidine (decitabine) in hematopoietic malignancies. Blood. 2004;103(5):1635–40.PubMedCrossRefGoogle Scholar
  116. Jackson-Grusby L, et al. Mutagenicity of 5-aza-2′-deoxycytidine is mediated by the mammalian DNA methyltransferase. Proc Natl Acad Sci. 1997;94(9):4681–5.PubMedCrossRefGoogle Scholar
  117. Jahangeer S, et al. β-Adrenergic receptor induction in HeLa cells: synergistic effect of 5-azacytidine and butyrate. Biochem Biophys Res Commun. 1982;108(4):1434–40.PubMedCrossRefGoogle Scholar
  118. Jazbutyte V, et al. MicroRNA-22 increases senescence and activates cardiac fibroblasts in the aging heart. Age. 2013;35(3):747–62.PubMedCrossRefGoogle Scholar
  119. Jiang X-Y, et al. Inhibition of gata4 and Tbx5 by nicotine-mediated DNA methylation in myocardial differentiation. Stem Cell Rep. 2017;8(2):290–304.CrossRefGoogle Scholar
  120. Jones PA. Cancer: death and methylation. Nature. 2001;409(6817):141–4.PubMedCrossRefGoogle Scholar
  121. Jones PA, Liang G. Rethinking how DNA methylation patterns are maintained. Nat Rev Genet. 2009;10(11):805–11.PubMedPubMedCentralCrossRefGoogle Scholar
  122. Jones PL, et al. Methylated DNA and MeCP2 recruit histone deacetylase to repress transcription. Nat Genet. 1998;19(2):187–91.PubMedCrossRefGoogle Scholar
  123. Juergens RA, et al. Combination epigenetic therapy has efficacy in patients with refractory advanced non–small cell lung cancer. Cancer Discov. 2011;1(7):598–607.PubMedPubMedCentralCrossRefGoogle Scholar
  124. Kaneda R, et al. Genome-wide histone methylation profile for heart failure. Genes Cells. 2009;14(1):69–77.PubMedPubMedCentralCrossRefGoogle Scholar
  125. Kantarjian HM, et al. Results of decitabine (5-aza-2′ deoxycytidine) therapy in 130 patients with chronic myelogenous leukemia. Cancer. 2003;98(3):522–8.PubMedCrossRefGoogle Scholar
  126. Karpf AR, et al. Activation of the p53 DNA damage response pathway after inhibition of DNA methyltransferase by 5-aza-2′-deoxycytidine. Mol Pharmacol. 2001;59(4):751–7.PubMedCrossRefGoogle Scholar
  127. Kee HJ, Kook H. Roles and targets of class I and IIa histone deacetylases in cardiac hypertrophy. J Biomed Biotechnol. 2011;2011:928326.PubMedCrossRefGoogle Scholar
  128. Keshet I, et al. Evidence for an instructive mechanism of de novo methylation in cancer cells. Nat Genet. 2006;38(2):149–53.PubMedCrossRefGoogle Scholar
  129. Kijima M, et al. Trapoxin, an antitumor cyclic tetrapeptide, is an irreversible inhibitor of mammalian histone deacetylase. J Biol Chem. 1993;268(30):22429–35.PubMedGoogle Scholar
  130. Kim VN. MicroRNA biogenesis: coordinated cropping and dicing. Nat Rev Mol Cell Biol. 2005;6(5):376–85.PubMedCrossRefGoogle Scholar
  131. Kim YB, et al. Oxamflatin is a novel antitumor compound that inhibits mammalian histone deacetylase. Oncogene. 1999;18(15):2461–70.PubMedCrossRefGoogle Scholar
  132. Kim H, et al. TRF2 functions as a protein hub and regulates telomere maintenance by recognizing specific peptide motifs. Nat Struct Mol Biol. 2009;16(4):372–9.PubMedCrossRefGoogle Scholar
  133. Kim GH, et al. Epigenetic mechanisms of pulmonary hypertension. Pulm Circ. 2011;1(3):347–56.PubMedPubMedCentralCrossRefGoogle Scholar
  134. Knudson AG. Karnofsky memorial lecture. Hereditary cancer: theme and variations. J Clin Oncol. 1997;15(10):3280–7.PubMedCrossRefGoogle Scholar
  135. Kong W, et al. Strategies for profiling microRNA expression. J Cell Physiol. 2009;218(1):22–5.PubMedCrossRefPubMedCentralGoogle Scholar
  136. Kornienko AE, et al. Gene regulation by the act of long non-coding RNA transcription. BMC Biol. 2013;11(1):59.PubMedPubMedCentralCrossRefGoogle Scholar
  137. Kowalczyk MS, et al. Molecular biology: RNA discrimination. Nature. 2012;482(7385):310–1.PubMedCrossRefPubMedCentralGoogle Scholar
  138. Kroh EM, et al. Analysis of circulating microRNA biomarkers in plasma and serum using quantitative reverse transcription-PCR (qRT-PCR). Methods. 2010;50(4):298–301.PubMedPubMedCentralCrossRefGoogle Scholar
  139. Lagos-Quintana M, et al. Identification of tissue-specific microRNAs from mouse. Curr Biol. 2002;12(9):735–9.CrossRefGoogle Scholar
  140. Laird PW. The power and the promise of DNA methylation markers. Nat Rev Cancer. 2003;3(4):253.PubMedCrossRefGoogle Scholar
  141. Laird PW. Principles and challenges of genome-wide DNA methylation analysis. Nat Rev Genet. 2010;11(3):191–203.PubMedCrossRefPubMedCentralGoogle Scholar
  142. Landsverk HB, et al. The protein phosphatase 1 regulator PNUTS is a new component of the DNA damage response. EMBO Rep. 2010;11(11):868–75.PubMedPubMedCentralCrossRefGoogle Scholar
  143. Larsen F, et al. CpG islands as gene markers in the human genome. Genomics. 1992;13(4):1095–107.PubMedCrossRefGoogle Scholar
  144. Lau OD, et al. HATs off: selective synthetic inhibitors of the histone acetyltransferases p300 and PCAF. Mol Cell. 2000;5(3):589–95.PubMedCrossRefGoogle Scholar
  145. Lawson C, et al. Microvesicles and exosomes: new players in metabolic and cardiovascular disease. J Endocrinol. 2016;228(2):R57–71.PubMedPubMedCentralCrossRefGoogle Scholar
  146. Lee Y, et al. The nuclear RNase III Drosha initiates microRNA processing. Nature. 2003;425(6956):415–9.CrossRefGoogle Scholar
  147. Lee HA, et al. Histone deacetylase inhibition attenuates transcriptional activity of mineralocorticoid receptor through its acetylation and prevents development of hypertension. Circ Res. 2013;112(7):1004–12.PubMedCrossRefGoogle Scholar
  148. Li Q, et al. Attenuation of microRNA-1 derepresses the cytoskeleton regulatory protein twinfilin-1 to provoke cardiac hypertrophy. J Cell Sci. 2010;123(14):2444–52.PubMedCrossRefGoogle Scholar
  149. Li M, et al. Emergence of fibroblasts with a proinflammatory epigenetically altered phenotype in severe hypoxic pulmonary hypertension. J Immunol. 2011;187(5):2711–22.PubMedPubMedCentralCrossRefGoogle Scholar
  150. Liang G, et al. Analysis of gene induction in human fibroblasts and bladder cancer cells exposed to the methylation inhibitor 5-aza-2′-deoxycytidine. Cancer Res. 2002;62(4):961–6.PubMedGoogle Scholar
  151. Lin RJ, et al. Role of the histone deacetylase complex in acute promyelocytic leukaemia. Nature. 1998;391(6669):811–4.PubMedCrossRefGoogle Scholar
  152. Lin H, et al. Suppression of intestinal neoplasia by deletion of Dnmt3b. Mol Cell Biol. 2006;26(8):2976–83.PubMedPubMedCentralCrossRefGoogle Scholar
  153. Lopez-Serra L, et al. A profile of methyl-CpG binding domain protein occupancy of hypermethylated promoter CpG islands of tumor suppressor genes in human cancer. Cancer Res. 2006;66(17):8342–6.PubMedCrossRefGoogle Scholar
  154. Loscalzo J, Handy DE. Epigenetic modifications: basic mechanisms and role in cardiovascular disease (2013 Grover conference series). Pulm Circ. 2014;4(2):169–74.PubMedPubMedCentralCrossRefGoogle Scholar
  155. Lubbert M. DNA methylation inhibitors in the treatment of leukemias, myelodysplastic syndromes and hemoglobinopathies: clinical results and possible mechanisms of action. Curr Top Microbiol Immunol. 2000;249:135.PubMedGoogle Scholar
  156. Lund G, et al. DNA methylation polymorphisms precede any histological sign of atherosclerosis in mice lacking apolipoprotein E. J Biol Chem. 2004;279(28):29147–54.PubMedCrossRefGoogle Scholar
  157. Maegawa S, et al. Caloric restriction delays age-related methylation drift. Nat Commun. 2017;8(1):539.PubMedPubMedCentralCrossRefGoogle Scholar
  158. Majumdar G, et al. Pan-histone deacetylase inhibitors regulate signaling pathways involved in proliferative and pro-inflammatory mechanisms in H9c2 cells. BMC Genomics. 2012;13:709.PubMedPubMedCentralCrossRefGoogle Scholar
  159. Malkin D. p53 and the Li-Fraumeni syndrome. Cancer Genet Cytogenet. 1993;66(2):83–92.PubMedCrossRefGoogle Scholar
  160. Manabe I, Owens GK. Recruitment of serum response factor and hyperacetylation of histones at smooth muscle-specific regulatory regions during differentiation of a novel P19-derived in vitro smooth muscle differentiation system. Circ Res. 2001;88(11):1127–34.PubMedCrossRefGoogle Scholar
  161. Marks PA, et al. Histone deacetylases. Curr Opin Pharmacol. 2003;3(4):344–51.PubMedCrossRefGoogle Scholar
  162. Martin L, et al. Systematic reconstruction of RNA functional motifs with high-throughput microfluidics. Nat Methods. 2012;9(12):1192–4.PubMedCrossRefGoogle Scholar
  163. McDonald OG, et al. Control of SRF binding to CArG box chromatin regulates smooth muscle gene expression in vivo. J Clin Invest. 2006;116(1):36–48.PubMedPubMedCentralCrossRefGoogle Scholar
  164. McMurray JJ, Pfeffer MA. Heart failure. Lancet. 2005;365(9474):1877–89.PubMedCrossRefGoogle Scholar
  165. Mestdagh P, et al. Evaluation of quantitative miRNA expression platforms in the microRNA quality control (miRQC) study. Nat Methods. 2014;11(8):809–15.PubMedCrossRefGoogle Scholar
  166. Mikkelsen TS, et al. Genome-wide maps of chromatin state in pluripotent and lineage-committed cells. Nature. 2007;448(7153):553–60.PubMedPubMedCentralCrossRefGoogle Scholar
  167. Milne TA, et al. Chromatin immunoprecipitation (ChIP) for analysis of histone modifications and chromatin-associated proteins. Methods Mol Biol (Clifton, N.J.). 2009;538:409–23.PubMedCentralCrossRefPubMedGoogle Scholar
  168. Mitchell PS, et al. Circulating microRNAs as stable blood-based markers for cancer detection. Proc Natl Acad Sci. 2008;105(30):10513–8.PubMedCrossRefGoogle Scholar
  169. Miyamoto K, Ushijima T. Diagnostic and therapeutic applications of epigenetics. Jpn J Clin Oncol. 2005;35(6):293–301.PubMedCrossRefGoogle Scholar
  170. Moazed D. Small RNAs in transcriptional gene silencing and genome defence. Nature. 2009;457(7228):413–20.PubMedPubMedCentralCrossRefGoogle Scholar
  171. Moncada S, Higgs A. The L-arginine-nitric oxide pathway. N Engl J Med. 1993;329(27):2002–12.PubMedPubMedCentralCrossRefGoogle Scholar
  172. Montgomery RL, et al. Histone deacetylases 1 and 2 redundantly regulate cardiac morphogenesis, growth, and contractility. Genes Dev. 2007;21(14):1790–802.PubMedPubMedCentralCrossRefGoogle Scholar
  173. Monzon J, et al. CDKN2A mutations in multiple primary melanomas. N Engl J Med. 1998;338(13):879–87.PubMedCrossRefGoogle Scholar
  174. Movassagh M, et al. Differential DNA methylation correlates with differential expression of angiogenic factors in human heart failure. PLoS One. 2010;5(1):e8564.PubMedPubMedCentralCrossRefGoogle Scholar
  175. Mu S, et al. Epigenetic modulation of the renal beta-adrenergic-WNK4 pathway in salt-sensitive hypertension. Nat Med. 2011;17(5):573–80.PubMedCrossRefGoogle Scholar
  176. Nagy Z, Tora L. Distinct GCN5/PCAF-containing complexes function as co-activators and are involved in transcription factor and global histone acetylation. Oncogene. 2007;26(37):5341–57.PubMedCrossRefGoogle Scholar
  177. Napoli C, Ignarro LJ. Nitric oxide and pathogenic mechanisms involved in the development of vascular diseases. Arch Pharm Res. 2009;32(8):1103–8.PubMedCrossRefGoogle Scholar
  178. Nemerovski CW, et al. Vitamin D and cardiovascular disease. Pharmacother: J Hum Pharmacol Drug Ther. 2009;29(6):691–708.CrossRefGoogle Scholar
  179. Ng H-H, et al. MBD2 is a transcriptional repressor belonging to the MeCP1 histone deacetylase complex. Nat Genet. 1999;23:58–61.PubMedCrossRefGoogle Scholar
  180. Niwa Y, et al. Methylation silencing of SOCS-3 promotes cell growth and migration by enhancing JAK/STAT and FAK signalings in human hepatocellular carcinoma. Oncogene. 2005;24(42):6406–17.PubMedCrossRefGoogle Scholar
  181. O’Geen H, et al. Using ChIP-seq technology to generate high-resolution profiles of histone modifications. Epigenetics Protoc. 2011;791:265–86.CrossRefGoogle Scholar
  182. Oishi K. Plasminogen activator inhibitor-1 and the circadian clock in metabolic disorders. Clin Exp Hypertens. 2009;31(3):208–19.PubMedCrossRefGoogle Scholar
  183. Oka D, et al. The presence of aberrant DNA methylation in noncancerous esophageal mucosae in association with smoking history. Cancer. 2009;115(15):3412–26.PubMedCrossRefGoogle Scholar
  184. Okano M, et al. DNA methyltransferases Dnmt3a and Dnmt3b are essential for de novo methylation and mammalian development. Cell. 1999;99(3):247–57.PubMedCrossRefGoogle Scholar
  185. Olsen EA, et al. Phase IIb multicenter trial of vorinostat in patients with persistent, progressive, or treatment refractory cutaneous T-cell lymphoma. J Clin Oncol. 2007;25(21):3109–15.PubMedCrossRefGoogle Scholar
  186. Omodei D, Fontana L. Calorie restriction and prevention of age-associated chronic disease. FEBS Lett. 2011;585(11):1537–42.PubMedPubMedCentralCrossRefGoogle Scholar
  187. Ovchinnikova ES, et al. Signature of circulating microRNAs in patients with acute heart failure. Eur J Heart Fail. 2016;18(4):414–23.PubMedCrossRefGoogle Scholar
  188. Park PJ. ChIP–seq: advantages and challenges of a maturing technology. Nat Rev Genet. 2009;10(10):669–80.PubMedPubMedCentralCrossRefGoogle Scholar
  189. Paul CL, Clark SJ. Cytosine methylation: quantitation by automated genomic sequencing and GENESCAN analysis. BioTechniques. 1996;21(1):126–33.PubMedCrossRefGoogle Scholar
  190. Perez-Campo FM, et al. The histone acetyl transferase activity of monocytic leukemia zinc finger is critical for the proliferation of hematopoietic precursors. Blood. 2009;113(20):4866–74.PubMedPubMedCentralCrossRefGoogle Scholar
  191. Petretto E, et al. Integrated genomic approaches implicate osteoglycin (Ogn) in the regulation of left ventricular mass. Nat Genet. 2008;40(5):546–52.PubMedPubMedCentralCrossRefGoogle Scholar
  192. Piekarz RL, et al. Phase II multi-institutional trial of the histone deacetylase inhibitor romidepsin as monotherapy for patients with cutaneous T-cell lymphoma. J Clin Oncol. 2009;27(32):5410–7.PubMedPubMedCentralCrossRefGoogle Scholar
  193. Plongthongkum N, et al. Advances in the profiling of DNA modifications: cytosine methylation and beyond. Nat Rev Genet. 2014;15(10):647–61.PubMedCrossRefGoogle Scholar
  194. Plumb JA, et al. Reversal of drug resistance in human tumor xenografts by 2′-deoxy-5-azacytidine-induced demethylation of the hMLH1 gene promoter. Cancer Res. 2000;60(21):6039–44.Google Scholar
  195. Portela A, Esteller M. Epigenetic modifications and human disease. Nat Biotechnol. 2010;28(10):1057–68.PubMedCrossRefGoogle Scholar
  196. Post WS, et al. Methylation of the estrogen receptor gene is associated with aging and atherosclerosis in the cardiovascular system. Cardiovasc Res. 1999;43(4):985–91.CrossRefGoogle Scholar
  197. Qiu T, et al. Effects of treatment with histone deacetylase inhibitors in solid tumors: a review based on 30 clinical trials. Future Oncol. 2013;9(2):255–69.PubMedCrossRefGoogle Scholar
  198. Rao PK, et al. Loss of cardiac microRNA-mediated regulation leads to dilated cardiomyopathy and heart failure. Circ Res. 2009;105(6):585–94.PubMedPubMedCentralCrossRefGoogle Scholar
  199. Raposo G, Stoorvogel W. Extracellular vesicles: exosomes, microvesicles, and friends. J Cell Biol. 2013;200(4):373–83.PubMedPubMedCentralCrossRefGoogle Scholar
  200. Ravasi T, et al. Experimental validation of the regulated expression of large numbers of non-coding RNAs from the mouse genome. Genome Res. 2006;16(1):11–9.PubMedPubMedCentralCrossRefGoogle Scholar
  201. Razin A, Riggs AD. DNA methylation and gene function. Science. 1980;210(4470):604–10.PubMedPubMedCentralCrossRefGoogle Scholar
  202. Reddy MA, Natarajan R. Epigenetic mechanisms in diabetic vascular complications. Cardiovasc Res. 2011;90(3):421–9.PubMedPubMedCentralCrossRefGoogle Scholar
  203. Reik W, Lewis A. Co-evolution of X-chromosome inactivation and imprinting in mammals. Nat Rev Genet. 2005;6(5):403–10.PubMedCrossRefGoogle Scholar
  204. Reik W, Walter J. Genomic imprinting: parental influence on the genome. Nat Rev Genet. 2001;2(1):21–32.PubMedCrossRefGoogle Scholar
  205. Ren B, et al. Genome-wide location and function of DNA binding proteins. Science. 2000;290(5500):2306–9.PubMedCrossRefGoogle Scholar
  206. Riggs AD. X inactivation, differentiation, and DNA methylation. Cytogenet Genome Res. 1975;14(1):9–25.CrossRefGoogle Scholar
  207. Robert M-F, et al. DNMT1 is required to maintain CpG methylation and aberrant gene silencing in human cancer cells. Nat Genet. 2003;33(1):61–5.PubMedCrossRefGoogle Scholar
  208. Roberts RJ, et al. A nomenclature for restriction enzymes, DNA methyltransferases, homing endonucleases and their genes. Nucleic Acids Res. 2003;31(7):1805–12.PubMedPubMedCentralCrossRefGoogle Scholar
  209. Robertson KD. DNA methylation and human disease. Nat Rev Genet. 2005;6(8):597–610.PubMedCrossRefGoogle Scholar
  210. Rochette L, et al. Nitric oxide synthase inhibition and oxidative stress in cardiovascular diseases: possible therapeutic targets? Pharmacol Ther. 2013;140(3):239–57.PubMedCrossRefGoogle Scholar
  211. Roger VL. Epidemiology of heart failure. Circ Res. 2013;113(6):646–59.PubMedPubMedCentralCrossRefGoogle Scholar
  212. Rountree MR, et al. DNMT1 binds HDAC2 and a new co-repressor, DMAP1, to form a complex at replication foci. Nat Genet. 2000;25(3):269–77.PubMedCrossRefGoogle Scholar
  213. Rousseau E, et al. CDKN2A, CDKN2B and p14 ARF are frequently and differentially methylated in ependymal tumours. Neuropathol Appl Neurobiol. 2003;29(6):574–83.PubMedCrossRefGoogle Scholar
  214. Roy S, et al. MicroRNA expression in response to murine myocardial infarction: miR-21 regulates fibroblast metalloprotease-2 via phosphatase and tensin homologue. Cardiovasc Res. 2009;82(1):21–9.PubMedPubMedCentralCrossRefGoogle Scholar
  215. Rush LJ, Plass C. Restriction landmark genomic scanning for DNA methylation in cancer: past, present, and future applications. Anal Biochem. 2002;307(2):191–201.PubMedCrossRefGoogle Scholar
  216. Sadri R, Hornsby PJ. Rapid analysis of DNA methylation using new restriction enzyme sites created by bisulfite modification. Nucleic Acids Res. 1996;24(24):5058–9.PubMedPubMedCentralCrossRefGoogle Scholar
  217. Sato N, et al. Frequent hypomethylation of multiple genes overexpressed in pancreatic ductal adenocarcinoma. Cancer Res. 2003;63(14):4158–66.PubMedGoogle Scholar
  218. Saxonov S, et al. A genome-wide analysis of CpG dinucleotides in the human genome distinguishes two distinct classes of promoters. Proc Natl Acad Sci. 2006;103(5):1412–7.PubMedCrossRefGoogle Scholar
  219. Sayed D, et al. MicroRNAs play an essential role in the development of cardiac hypertrophy. Circ Res. 2007;100(3):416–24.PubMedCrossRefGoogle Scholar
  220. Segura-Pacheco B, et al. Global DNA hypermethylation-associated cancer chemotherapy resistance and its reversion with the demethylating agent hydralazine. J Transl Med. 2006;4(1):32.PubMedPubMedCentralCrossRefGoogle Scholar
  221. Selker EU, et al. The methylated component of the Neurospora crassa genome. Nature. 2003;422(6934):893–7.PubMedCrossRefGoogle Scholar
  222. Shapiro R, et al. Reactions of uracil and cytosine derivatives with sodium bisulfite. J Am Chem Soc. 1970;92(2):422–4.CrossRefGoogle Scholar
  223. Shingara J, et al. An optimized isolation and labeling platform for accurate microRNA expression profiling. RNA. 2005;11(9):1461–70.PubMedPubMedCentralCrossRefGoogle Scholar
  224. Shirodkar AV, Marsden PA. Epigenetics in cardiovascular disease. Curr Opin Cardiol. 2011;26(3):209.PubMedPubMedCentralCrossRefGoogle Scholar
  225. Shu J, et al. Dynamic and modularized microRNA regulation and its implication in human cancers. Sci Rep. 2017;7(1):13356.PubMedPubMedCentralCrossRefGoogle Scholar
  226. Silverman LR, et al. Randomized controlled trial of azacitidine in patients with the myelodysplastic syndrome: a study of the cancer and leukemia group B. J Clin Oncol. 2002;20(10):2429–40.PubMedCrossRefGoogle Scholar
  227. Singer-Sam J, et al. A quantitative HpaII-PCR assay to measure methylation of DNA from a small number of cells. Nucleic Acids Res. 1990;18(3):687.PubMedPubMedCentralCrossRefGoogle Scholar
  228. Singh N, et al. Molecular modeling and molecular dynamics studies of hydralazine with human DNA methyltransferase 1. Chem Med Chem. 2009;4(5):792–9.PubMedCrossRefGoogle Scholar
  229. Sobulo OM, et al. MLL is fused to CBP, a histone acetyltransferase, in therapy-related acute myeloid leukemia with a t (11; 16)(q23; p13. 3). Proc Natl Acad Sci. 1997;94(16):8732–7.PubMedCrossRefGoogle Scholar
  230. Song F, et al. Association of tissue-specific differentially methylated regions (TDMs) with differential gene expression. Proc Natl Acad Sci U S A. 2005;102(9):3336–41.PubMedPubMedCentralCrossRefGoogle Scholar
  231. Šorm F, et al. 5-Azacytidine, a new, highly effective cancerostatic. Cell Mol Life Sci. 1964;20(4):202–3.CrossRefGoogle Scholar
  232. Spencer VA, et al. Chromatin immunoprecipitation: a tool for studying histone acetylation and transcription factor binding. Methods. 2003;31(1):67–75.PubMedCrossRefGoogle Scholar
  233. Stenvinkel P, et al. Impact of inflammation on epigenetic DNA methylation–a novel risk factor for cardiovascular disease? J Intern Med. 2007;261(5):488–99.PubMedCrossRefGoogle Scholar
  234. Stewart D, et al. A phase I pharmacokinetic and pharmacodynamic study of the DNA methyltransferase 1 inhibitor MG98 administered twice weekly. Ann Oncol. 2003;14(5):766–74.PubMedCrossRefGoogle Scholar
  235. Suzuki H, et al. Epigenetic inactivation of SFRP genes allows constitutive WNT signaling in colorectal cancer. Nat Genet. 2004;36(4):417–22.PubMedCrossRefGoogle Scholar
  236. Suzuki K, et al. Global DNA demethylation in gastrointestinal cancer is age dependent and precedes genomic damage. Cancer Cell. 2006;9(3):199–207.PubMedCrossRefGoogle Scholar
  237. Swedberg K, et al. Guidelines for the diagnosis and treatment of chronic heart failure: executive summary (update 2005). Eur Heart J. 2005;26(11):1115–40.CrossRefPubMedGoogle Scholar
  238. Thiagalingam S, et al. Loss of heterozygosity as a predictor to map tumor suppressor genes in cancer: molecular basis of its occurrence. Curr Opin Oncol. 2002;14(1):65–72.PubMedCrossRefGoogle Scholar
  239. Thiagarajan D, et al. Mechanisms of transcription factor acetylation and consequences in hearts. Biochim Biophys Acta. 2016;1862(12):2221–31.PubMedPubMedCentralCrossRefGoogle Scholar
  240. Thum T, et al. MicroRNA-21 contributes to myocardial disease by stimulating MAP kinase signalling in fibroblasts. Nature. 2008;456(7224):980–4.CrossRefGoogle Scholar
  241. Tijsen AJ, et al. Circulating microRNAs as diagnostic biomarkers for cardiovascular diseases. Am J Phys Heart Circ Phys. 2012;303(9):H1085–95.Google Scholar
  242. Tobi EW, et al. DNA methylation differences after exposure to prenatal famine are common and timing- and sex-specific. Hum Mol Genet. 2009;18(21):4046–53.PubMedPubMedCentralCrossRefGoogle Scholar
  243. Toyota M, Issa J-PJ. CpG island methylator phenotypes in aging and cancer. Semin Cancer Biol. 1999;9(5):349–57.PubMedCrossRefGoogle Scholar
  244. Trivedi MS, et al. Short-term sleep deprivation leads to decreased systemic redox metabolites and altered epigenetic status. PLoS One. 2017;12(7):e0181978.PubMedPubMedCentralCrossRefGoogle Scholar
  245. Tsai M-C, et al. Long noncoding RNA as modular scaffold of histone modification complexes. Science. 2010;329(5992):689–93.PubMedPubMedCentralCrossRefGoogle Scholar
  246. Turunen MP, et al. Epigenetics and atherosclerosis. Biochim Biophys Acta (BBA)-Gen Subj. 2009;1790(9):886–91.CrossRefGoogle Scholar
  247. Usui M, et al. Increased endogenous nitric oxide synthase inhibitor in patients with congestive heart failure. Life Sci. 1998;62(26):2425–30.PubMedCrossRefGoogle Scholar
  248. Usui T, et al. HDAC4 mediates development of hypertension via vascular inflammation in spontaneous hypertensive rats. Am J Physiol Heart Circ Physiol. 2012;302(9):H1894–904.PubMedCrossRefGoogle Scholar
  249. Vaissière T, et al. Epigenetic interplay between histone modifications and DNA methylation in gene silencing. Mutat Res/Rev Mutat Res. 2008;659(1):40–8.CrossRefGoogle Scholar
  250. Valencia A, et al. Wnt signaling pathway is epigenetically regulated by methylation of Wnt antagonists in acute myeloid leukemia. Leukemia. 2009;23(9):1658–66.PubMedCrossRefGoogle Scholar
  251. Van Aelst LN, et al. Osteoglycin prevents cardiac dilatation and dysfunction after myocardial infarction through infarct collagen strengthening. Circ Res. 2014;116:425–36.PubMedCrossRefGoogle Scholar
  252. Varrone F, et al. The circulating level of FABP3 is an indirect biomarker of microRNA-1. J Am Coll Cardiol. 2013;61(1):88–95.PubMedCrossRefGoogle Scholar
  253. Villar AV, et al. Myocardial and circulating levels of microRNA-21 reflect left ventricular fibrosis in aortic stenosis patients. Int J Cardiol. 2013;167(6):2875–81.PubMedCrossRefGoogle Scholar
  254. Voellenkle C, et al. MicroRNA signatures in peripheral blood mononuclear cells of chronic heart failure patients. Physiol Genomics. 2010;42(3):420–6.PubMedCrossRefPubMedCentralGoogle Scholar
  255. Waddington C. The epigenetics of birds. New York: Cambridge University Press; 1952.Google Scholar
  256. Wadhwa PD, et al. Developmental origins of health and disease: brief history of the approach and current focus on epigenetic mechanisms. Semin Reprod Med. 2009;27(5):358–68.PubMedPubMedCentralCrossRefGoogle Scholar
  257. Wagner JM, et al. Histone deacetylase (HDAC) inhibitors in recent clinical trials for cancer therapy. Clin Epigenetics. 2010;1(3):117.PubMedPubMedCentralCrossRefGoogle Scholar
  258. Wang LQ, Chim CS. DNA methylation of tumor-suppressor miRNA genes in chronic lymphocytic leukemia. Epigenomics. 2015;7(3):461–73.PubMedCrossRefPubMedCentralGoogle Scholar
  259. Wang Y, et al. Dysregulation of histone acetyltransferases and deacetylases in cardiovascular diseases. Oxidative Med Cell Longev. 2014;2014:641979.Google Scholar
  260. Waterland RA, Jirtle RL. Transposable elements: targets for early nutritional effects on epigenetic gene regulation. Mol Cell Biol. 2003;23(15):5293–300.PubMedPubMedCentralCrossRefGoogle Scholar
  261. Waterland RA, Michels KB. Epigenetic epidemiology of the developmental origins hypothesis. Annu Rev Nutr. 2007;27:363–88.PubMedCrossRefGoogle Scholar
  262. Weber J, et al. Expression of the MAGE-1 tumor antigen is up-regulated by the demethylating agent 5-aza-2′-deoxycytidine. Cancer Res. 1994;54(7):1766–71.PubMedPubMedCentralGoogle Scholar
  263. Weber M, et al. Chromosome-wide and promoter-specific analyses identify sites of differential DNA methylation in normal and transformed human cells. Nat Genet. 2005;37(8):853–62.PubMedCrossRefGoogle Scholar
  264. Weber M, et al. Distribution, silencing potential and evolutionary impact of promoter DNA methylation in the human genome. Nat Genet. 2007;39(4):457–66.PubMedCrossRefGoogle Scholar
  265. West AC, Johnstone RW. New and emerging HDAC inhibitors for cancer treatment. J Clin Invest. 2014;124(1):30–9.PubMedPubMedCentralCrossRefGoogle Scholar
  266. Whittaker SJ, et al. Final results from a multicenter, international, pivotal study of romidepsin in refractory cutaneous T-cell lymphoma. J Clin Oncol. 2010;28(29):4485–91.PubMedCrossRefGoogle Scholar
  267. Widschwendter M, et al. DNA hypomethylation and ovarian cancer biology. Cancer Res. 2004;64(13):4472–80.PubMedCrossRefGoogle Scholar
  268. Willenbrock H, et al. Quantitative miRNA expression analysis: comparing microarrays with next-generation sequencing. RNA. 2009;15(11):2028–34.PubMedPubMedCentralCrossRefGoogle Scholar
  269. Wilson Tang WH, et al. Differential effects of arginine methylation on diastolic dysfunction and disease progression in patients with chronic systolic heart failure. Eur Heart J. 2008;29(20):2506–13.PubMedCentralCrossRefPubMedGoogle Scholar
  270. Wimalawansa SJ. Vitamin D and cardiovascular diseases: causality. J Steroid Biochem Mol Biol. 2016;175:29–43.PubMedCrossRefGoogle Scholar
  271. Xiao H, et al. Both Sp1 and Sp3 are responsible for p21waf1 promoter activity induced by histone deacetylase inhibitor in NIH3T3 cells. J Cell Biochem. 1999;73(3):291–302.PubMedCrossRefGoogle Scholar
  272. Xie M, Hill JA. HDAC-dependent ventricular remodeling. Trends Cardiovasc Med. 2013;23(6):229–35.PubMedPubMedCentralCrossRefGoogle Scholar
  273. Yamada Y, et al. Opposing effects of DNA hypomethylation on intestinal and liver carcinogenesis. Proc Natl Acad Sci U S A. 2005;102(38):13580–5.PubMedPubMedCentralCrossRefGoogle Scholar
  274. Yamashita K, et al. Pharmacologic unmasking of epigenetically silenced tumor suppressor genes in esophageal squamous cell carcinoma. Cancer Cell. 2002;2(6):485–95.PubMedCrossRefGoogle Scholar
  275. Yanazume T, et al. Cardiac p300 is involved in myocyte growth with decompensated heart failure. Mol Cell Biol. 2003;23(10):3593–606.PubMedPubMedCentralCrossRefGoogle Scholar
  276. Yang XJ, Seto E. HATs and HDACs: from structure, function and regulation to novel strategies for therapy and prevention. Oncogene. 2007;26(37):5310–8.CrossRefGoogle Scholar
  277. Yang XJ, Seto E. Lysine acetylation: codified crosstalk with other posttranslational modifications. Mol Cell. 2008;31(4):449–61.PubMedPubMedCentralCrossRefGoogle Scholar
  278. Yang X, et al. Targeting DNA methylation for epigenetic therapy. Trends Pharmacol Sci. 2010;31(11):536–46.PubMedPubMedCentralCrossRefGoogle Scholar
  279. Yang Q, et al. Pulmonary artery smooth muscle cell proliferation and migration in fetal lambs acclimatized to high-altitude long-term hypoxia: role of histone acetylation. Am J Physiol Lung Cell Mol Physiol. 2012;303(11):L1001–10.PubMedPubMedCentralCrossRefGoogle Scholar
  280. Yoder JA, et al. Cytosine methylation and the ecology of intragenomic parasites. Trends Genet. 1997;13(8):335–40.PubMedCrossRefGoogle Scholar
  281. Yoo CB, et al. Long-term epigenetic therapy with oral zebularine has minimal side effects and prevents intestinal tumors in mice. Cancer Prev Res. 2008;1(4):233–40.CrossRefGoogle Scholar
  282. Yoshida M, et al. Potent and specific inhibition of mammalian histone deacetylase both in vivo and in vitro by trichostatin A. J Biol Chem. 1990;265(28):17174–9.PubMedGoogle Scholar
  283. Yoshikawa H, et al. SOCS-1, a negative regulator of the JAK/STAT pathway, is silenced by methylation in human hepatocellular carcinoma and shows growth-suppression activity. Nat Genet. 2001;28(1):29–35.PubMedGoogle Scholar
  284. Zaina S, et al. Nutrition and aberrant DNA methylation patterns in atherosclerosis: more than just hyperhomocysteinemia? J Nutr. 2005;135(1):5–8.PubMedCrossRefGoogle Scholar
  285. Zhang Y, et al. Model-based analysis of ChIP-Seq (MACS). Genome Biol. 2008;9(9):R137.PubMedPubMedCentralCrossRefGoogle Scholar
  286. Zhao W, et al. Abnormal activation of the synuclein-gamma gene in hepatocellular carcinomas by epigenetic alteration. Int J Oncol. 2006;28(5):1081–8.PubMedGoogle Scholar
  287. Zhao Y, et al. Dysregulation of cardiogenesis, cardiac conduction, and cell cycle in mice lacking miRNA-1-2. Cell. 2007;129(2):303–17.PubMedCrossRefGoogle Scholar
  288. Zhong J, et al. Cardiac autonomic dysfunction: particulate air pollution effects are modulated by epigenetic immunoregulation of toll-like receptor 2 and dietary flavonoid intake. J Am Heart Assoc. 2015;4(1):e001423.Google Scholar
  289. Zhu S, et al. Inactivation of monocarboxylate transporter MCT3 by DNA methylation in atherosclerosis. Circulation. 2005;112(9):1353–61.PubMedCrossRefGoogle Scholar
  290. Zilberman D, Henikoff S. Genome-wide analysis of DNA methylation patterns. Development. 2007;134(22):3959–65.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Nature Singapore Pte Ltd. 2018

Authors and Affiliations

  • Lu Qian Wang
    • 1
  • Kailash Singh
    • 1
  • Aung Moe Zaw
    • 1
  • Billy Kwok Chong Chow
    • 1
    Email author
  1. 1.School of Biological SciencesThe University of Hong KongHong KongChina

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