Skip to main content
Springer Nature Link
Log in

CpG Islands in Cancer: Heads, Tails, and Sides

  • Protocol
  • First Online:
CpG Islands

Part of the book series: Methods in Molecular Biology ((MIMB,volume 1766))

Abstract

DNA methylation is a dynamic epigenetic mark that characterizes different cellular developmental stages, including tissue-specific profiles. This CpG dinucleotide modification cooperates in the regulation of the output of the cellular genetic content, in both healthy and pathological conditions. According to endogenous and exogenous stimuli, DNA methylation is involved in gene transcription, alternative splicing, imprinting, X-chromosome inactivation, and control of transposable elements. When these dinucleotides are organized in dense regions are called CpG islands (CGIs), being commonly known as transcriptional regulatory regions frequently associated with the promoter region of several genes. In cancer, promoter DNA hypermethylation events sustained the mechanistic hypothesis of epigenetic transcriptional silencing of an increasing number of tumor suppressor genes. CGI hypomethylation-mediated reactivation of oncogenes was also documented in several cancer types. In this chapter, we aim to summarize the functional consequences of the differential DNA methylation at CpG dinucleotides in cancer, focused in CGIs. Interestingly, cancer methylome is being recently explored, looking for biomarkers for diagnosis, prognosis, and predictors of drug response.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution

Subscribe and save

Springer+ Basic
$34.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or eBook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Protocol
USD 49.95
Price excludes VAT (Canada)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 129.00
Price excludes VAT (Canada)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 169.99
Price excludes VAT (Canada)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 169.99
Price excludes VAT (Canada)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Similar content being viewed by others

References

  1. Esteller M (2008) Epigenetics in cancer. N Engl J Med 358(11):1148–1159

    Article  CAS  PubMed  Google Scholar 

  2. Arney KL, Fisher AG (2004) Epigenetic aspects of differentiation. J Cell Sci 117(Pt 19):4355–4363

    Article  CAS  PubMed  Google Scholar 

  3. Elango N, Yi SV (2008) DNA methylation and structural and functional bimodality of vertebrate promoters. Mol Biol Evol 25(8):1602–1608

    Article  CAS  PubMed  Google Scholar 

  4. Gonzalo S, Jaco I, Fraga MF, Chen T, Li E, Esteller M, Blasco MA (2006) DNA methyltransferases control telomere length and telomere recombination in mammalian cells. Nat Cell Biol 8(4):416–424

    Article  CAS  PubMed  Google Scholar 

  5. Schwartz S, Meshorer E, Ast G (2009) Chromatin organization marks exon-intron structure. Nat Struct Mol Biol 16(9):990–995

    Article  CAS  PubMed  Google Scholar 

  6. Hollister JD, Gaut BS (2009) Epigenetic silencing of transposable elements: a trade-off between reduced transposition and deleterious effects on neighboring gene expression. Genome Res 19(8):1419–1428

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Lee YC (2015) The role of piRNA-mediated epigenetic silencing in the population dynamics of transposable elements in Drosophila melanogaster. PLoS Genet 11(6):e1005269

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  8. Lyon MF (1962) Sex chromatin and gene action in the mammalian X-chromosome. Am J Hum Genet 14:135–148

    CAS  PubMed  PubMed Central  Google Scholar 

  9. Wutz A (2011) Gene silencing in X-chromosome inactivation: advances in understanding facultative heterochromatin formation. Nat Rev Genet 12(8):542–553

    Article  CAS  PubMed  Google Scholar 

  10. Reik W, Collick A, Norris ML, Barton SC, Surani MA (1987) Genomic imprinting determines methylation of parental alleles in transgenic mice. Nature 328(6127):248–251

    Article  CAS  PubMed  Google Scholar 

  11. Collick A, Reik W, Barton SC, Surani AH (1988) CpG methylation of an X-linked transgene is determined by somatic events postfertilization and not germline imprinting. Development 104(2):235–244

    CAS  PubMed  Google Scholar 

  12. Bird A (2002) DNA methylation patterns and epigenetic memory. Genes Dev 16(1):6–21

    Article  CAS  PubMed  Google Scholar 

  13. Bird AP (1986) CpG-rich islands and the function of DNA methylation. Nature 321(6067):209–213

    Article  CAS  PubMed  Google Scholar 

  14. Strichman-Almashanu LZ, Lee RS, Onyango PO, Perlman E, Flam F, Frieman MB, Feinberg AP (2002) A genome-wide screen for normally methylated human CpG islands that can identify novel imprinted genes. Genome Res 12(4):543–554

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Lovkvist C, Dodd IB, Sneppen K, Haerter JO (2016) DNA methylation in human epigenomes depends on local topology of CpG sites. Nucleic Acids Res 44(11):5125–5132

    Article  CAS  Google Scholar 

  16. Illingworth RS, Bird AP (2009) CpG islands—a rough guide. FEBS Lett 583(11):1713–1720

    Article  CAS  PubMed  Google Scholar 

  17. Wu H, Caffo B, Jaffee HA, Irizarry RA, Feinberg AP (2010) Redefining CpG islands using hidden Markov models. Biostatistics 11(3):499–514

    Article  PubMed  PubMed Central  Google Scholar 

  18. 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 U S A 103(5):1412–1417

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Ioshikhes IP, Zhang MQ (2000) Large-scale human promoter mapping using CpG islands. Nat Genet 26(1):61–63

    Article  CAS  PubMed  Google Scholar 

  20. Venter JC, Adams MD, Myers EW, Li PW, Mural RJ, Sutton GG, Smith HO, Yandell M, Evans CA, Holt RA, Gocayne JD, Amanatides P, Ballew RM, Huson DH, Wortman JR, Zhang Q, Kodira CD, Zheng XH, Chen L, Skupski M, Subramanian G, Thomas PD, Zhang J, Gabor Miklos GL, Nelson C, Broder S, Clark AG, Nadeau J, McKusick VA, Zinder N, Levine AJ, Roberts RJ, Simon M, Slayman C, Hunkapiller M, Bolanos R, Delcher A, Dew I, Fasulo D, Flanigan M, Florea L, Halpern A, Hannenhalli S, Kravitz S, Levy S, Mobarry C, Reinert K, Remington K, Abu-Threideh J, Beasley E, Biddick K, Bonazzi V, Brandon R, Cargill M, Chandramouliswaran I, Charlab R, Chaturvedi K, Deng Z, Di Francesco V, Dunn P, Eilbeck K, Evangelista C, Gabrielian AE, Gan W, Ge W, Gong F, Gu Z, Guan P, Heiman TJ, Higgins ME, Ji RR, Ke Z, Ketchum KA, Lai Z, Lei Y, Li Z, Li J, Liang Y, Lin X, Lu F, Merkulov GV, Milshina N, Moore HM, Naik AK, Narayan VA, Neelam B, Nusskern D, Rusch DB, Salzberg S, Shao W, Shue B, Sun J, Wang Z, Wang A, Wang X, Wang J, Wei M, Wides R, Xiao C, Yan C, Yao A, Ye J, Zhan M, Zhang W, Zhang H, Zhao Q, Zheng L, Zhong F, Zhong W, Zhu S, Zhao S, Gilbert D, Baumhueter S, Spier G, Carter C, Cravchik A, Woodage T, Ali F, An H, Awe A, Baldwin D, Baden H, Barnstead M, Barrow I, Beeson K, Busam D, Carver A, Center A, Cheng ML, Curry L, Danaher S, Davenport L, Desilets R, Dietz S, Dodson K, Doup L, Ferriera S, Garg N, Gluecksmann A, Hart B, Haynes J, Haynes C, Heiner C, Hladun S, Hostin D, Houck J, Howland T, Ibegwam C, Johnson J, Kalush F, Kline L, Koduru S, Love A, Mann F, May D, McCawley S, McIntosh T, McMullen I, Moy M, Moy L, Murphy B, Nelson K, Pfannkoch C, Pratts E, Puri V, Qureshi H, Reardon M, Rodriguez R, Rogers YH, Romblad D, Ruhfel B, Scott R, Sitter C, Smallwood M, Stewart E, Strong R, Suh E, Thomas R, Tint NN, Tse S, Vech C, Wang G, Wetter J, Williams S, Williams M, Windsor S, Winn-Deen E, Wolfe K, Zaveri J, Zaveri K, Abril JF, Guigo R, Campbell MJ, Sjolander KV, Karlak B, Kejariwal A, Mi H, Lazareva B, Hatton T, Narechania A, Diemer K, Muruganujan A, Guo N, Sato S, Bafna V, Istrail S, Lippert R, Schwartz R, Walenz B, Yooseph S, Allen D, Basu A, Baxendale J, Blick L, Caminha M, Carnes-Stine J, Caulk P, Chiang YH, Coyne M, Dahlke C, Mays A, Dombroski M, Donnelly M, Ely D, Esparham S, Fosler C, Gire H, Glanowski S, Glasser K, Glodek A, Gorokhov M, Graham K, Gropman B, Harris M, Heil J, Henderson S, Hoover J, Jennings D, Jordan C, Jordan J, Kasha J, Kagan L, Kraft C, Levitsky A, Lewis M, Liu X, Lopez J, Ma D, Majoros W, McDaniel J, Murphy S, Newman M, Nguyen T, Nguyen N, Nodell M, Pan S, Peck J, Peterson M, Rowe W, Sanders R, Scott J, Simpson M, Smith T, Sprague A, Stockwell T, Turner R, Venter E, Wang M, Wen M, Wu D, Wu M, Xia A, Zandieh A, Zhu X (2001) The sequence of the human genome. Science 291(5507):1304–1351

    Article  CAS  PubMed  Google Scholar 

  21. Lander ES, Linton LM, Birren B, Nusbaum C, Zody MC, Baldwin J, Devon K, Dewar K, Doyle M, FitzHugh W, Funke R, Gage D, Harris K, Heaford A, Howland J, Kann L, Lehoczky J, LeVine R, McEwan P, McKernan K, Meldrim J, Mesirov JP, Miranda C, Morris W, Naylor J, Raymond C, Rosetti M, Santos R, Sheridan A, Sougnez C, Stange-Thomann N, Stojanovic N, Subramanian A, Wyman D, Rogers J, Sulston J, Ainscough R, Beck S, Bentley D, Burton J, Clee C, Carter N, Coulson A, Deadman R, Deloukas P, Dunham A, Dunham I, Durbin R, French L, Grafham D, Gregory S, Hubbard T, Humphray S, Hunt A, Jones M, Lloyd C, McMurray A, Matthews L, Mercer S, Milne S, Mullikin JC, Mungall A, Plumb R, Ross M, Shownkeen R, Sims S, Waterston RH, Wilson RK, Hillier LDW, McPherson JD, Marra MA, Mardis ER, Fulton LA, Chinwalla AT, Pepin KH, Gish WR, Chissoe SL, Wendl MC, Delehaunty KD, Miner TL, Delehaunty A, Kramer JB, Cook LL, Fulton RS, Johnson DL, Minx PJ, Clifton SW, Hawkins T, Branscomb E, Predki P, Richardson P, Wenning S, Slezak T, Doggett N, Cheng J-F, Olsen A, Lucas S, Elkin C, Uberbacher E, Frazier M, Gibbs RA, Muzny DM, Scherer SE, Bouck JB, Sodergren EJ, Worley KC, Rives CM, Gorrell JH, Metzker ML, Naylor SL, Kucherlapati RS, Nelson DL, Weinstock GM, Sakaki Y, Fujiyama A, Hattori M, Yada T, Toyoda A, Itoh T, Kawagoe C, Watanabe H, Totoki Y, Taylor T, Weissenbach J, Heilig R, Saurin W, Artiguenave F, Brottier P, Bruls T, Pelletier E, Robert C, Wincker P, Rosenthal A, Platzer M, Nyakatura G, Taudien S, Rump A, Smith DR, Doucette-Stamm L, Rubenfield M, Weinstock K, Lee HM, Dubois JA, Yang H, Yu J, Wang J, Huang G, Jun G, Hood L, Lee R, Madan A, Qin S, Davis RW, Federspiel NA, Pia Abola A, Proctor MJ, Roe BA, Chen F, Pan H, Ramser J, Lehrach H, Richard R, Richard McCombie W, de la Bastide M, Dedhia N, Blöcker H, Hornischer K, Nordsiek G, Richa A, Aravind L, Bailey JA, Bateman A, Batzoglou S, Birney E, Bork P, Brown DG, Burge CB, Cerutti L, Chen H-C, Church D, Clamp M, Copley RR, Doerks T, Eddy SR, Eichler EE, Furey TS, Galagan J, Gilbert JGR, Harmon C, Hayashizaki Y, Haussler D, Hermjakob H, Hokamp K, Jang W, Steven Johnson L, Jones TA, Kasif S, Kaspryzk A, Kennedy S, James Kent W, Kitts P, Koonin EV, Korf I, Kulp D, Lancet D, Lowe TM, McLysaght A, Mikkelsen T, Moran JV, Mulder N, Pollara VJ, Ponting CP, Schuler G, Schultz J, Slater G, Smit AFA, Stupka E, Szustakowki J, Thierry-Mieg D, Thierry-Mieg J, Wagner L, Wallis J, Wheeler R, Williams A, Wolf YI, Wolfe KH, Yang SP, Yeh R-F, Collins F, Guyer MS, Peterson J, Felsenfeld A, Wetterstrand KA, Myers RM, Schmutz J, Dickson M, Grimwood J, Cox DR, Olson MV, Kaul R, Raymond C, Shimizu N, Kawasaki K, Minoshima S, Evans GA, Athanasiou M, Schultz R, Patrinos A, Morgan MJ (2001) Initial sequencing and analysis of the human genome. Nature 409(6822):860–921

    Article  CAS  PubMed  Google Scholar 

  22. Vavouri T, Lehner B (2012) Human genes with CpG island promoters have a distinct transcription-associated chromatin organization. Genome Biol 13(11):R110

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  23. Riggs AD (1975) X Inactivation, differentiation, and DNA methylation. Cytogenet Cell Genet 14(1):9–25

    Article  CAS  PubMed  Google Scholar 

  24. Holliday R, Pugh JE (1975) DNA modification mechanisms and gene activity during development. Science 187(4173):226–232

    Article  CAS  PubMed  Google Scholar 

  25. Kitamura E, Igarashi J, Morohashi A, Hida N, Oinuma T, Nemoto N, Song F, Ghosh S, Held WA, Yoshida-Noro C, Nagase H (2007) Analysis of tissue-specific differentially methylated regions (TDMs) in humans. Genomics 89(3):326–337

    Article  CAS  PubMed  Google Scholar 

  26. Lee HS, Chen ZJ (2001) Protein-coding genes are epigenetically regulated in Arabidopsis polyploids. Proc Natl Acad Sci U S A 98(12):6753–6758

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Suzuki H, Maruyama R, Yamamoto E, Kai M (2012) DNA methylation and microRNA dysregulation in cancer. Mol Oncol 6(6):567–578

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Kanwal R, Gupta S (2012) Epigenetic modifications in cancer. Clin Genet 81(4):303–311

    Article  CAS  PubMed  Google Scholar 

  29. Kang SH, Bang YJ, Im YH, Yang HK, Lee DA, Lee HY, Lee HS, Kim NK, Kim SJ (1999) Transcriptional repression of the transforming growth factor-beta type I receptor gene by DNA methylation results in the development of TGF-beta resistance in human gastric cancer. Oncogene 18(51):7280–7286

    Article  CAS  PubMed  Google Scholar 

  30. Baylin SB (2005) DNA methylation and gene silencing in cancer. Nat Clin Pract Oncol 2(Suppl 1):S4–11

    Article  CAS  PubMed  Google Scholar 

  31. Rodriguez C, Borgel J, Court F, Cathala G, Forne T, Piette J (2010) CTCF is a DNA methylation-sensitive positive regulator of the INK/ARF locus. Biochem Biophys Res Commun 392(2):129–134

    Article  CAS  PubMed  Google Scholar 

  32. Portela A, Esteller M (2010) Epigenetic modifications and human disease. Nat Biotechnol 28(10):1057–1068

    Article  CAS  PubMed  Google Scholar 

  33. Omura N, Mizuma M, MacGregor A, Hong SM, Ayars M, Almario JA, Borges M, Kanda M, Li A, Vincent A, Maitra A, Goggins M (2016) Overexpression of ankyrin1 promotes pancreatic cancer cell growth. Oncotarget 7(23):34977–34987

    Article  PubMed  PubMed Central  Google Scholar 

  34. McCarty G, Loeb DM (2015) Hypoxia-sensitive epigenetic regulation of an antisense-oriented lncRNA controls WT1 expression in myeloid leukemia cells. PLoS One 10(3):e0119837

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  35. Ferreira HJ, Heyn H, Moutinho C, Esteller M (2012) CpG island hypermethylation-associated silencing of small nucleolar RNAs in human cancer. RNA Biol 9(6):881–890

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Lev Maor G, Yearim A, Ast G (2015) The alternative role of DNA methylation in splicing regulation. Trends Genet 31(5):274–280

    Article  CAS  PubMed  Google Scholar 

  37. Gutierrez-Arcelus M, Ongen H, Lappalainen T, Montgomery SB, Buil A, Yurovsky A, Bryois J, Padioleau I, Romano L, Planchon A, Falconnet E, Bielser D, Gagnebin M, Giger T, Borel C, Letourneau A, Makrythanasis P, Guipponi M, Gehrig C, Antonarakis SE, Dermitzakis ET (2015) Tissue-specific effects of genetic and epigenetic variation on gene regulation and splicing. PLoS Genet 11(1):e1004958

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  38. Deaton AM, Webb S, Kerr AR, Illingworth RS, Guy J, Andrews R, Bird A (2011) Cell type-specific DNA methylation at intragenic CpG islands in the immune system. Genome Res 21(7):1074–1086

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Vizoso M, Ferreira HJ, Lopez-Serra P, Carmona FJ, Martinez-Cardus A, Girotti MR, Villanueva A, Guil S, Moutinho C, Liz J, Portela A, Heyn H, Moran S, Vidal A, Martinez-Iniesta M, Manzano JL, Fernandez-Figueras MT, Elez E, Munoz-Couselo E, Botella-Estrada R, Berrocal A, Ponten F, Oord J, Gallagher WM, Frederick DT, Flaherty KT, McDermott U, Lorigan P, Marais R, Esteller M (2015) Epigenetic activation of a cryptic TBC1D16 transcript enhances melanoma progression by targeting EGFR. Nat Med 21(7):741–750

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Wade PA (2001) Methyl CpG-binding proteins and transcriptional repression. BioEssays 23(12):1131–1137

    Article  CAS  PubMed  Google Scholar 

  41. Perez A, Castellazzi CL, Battistini F, Collinet K, Flores O, Deniz O, Ruiz ML, Torrents D, Eritja R, Soler-Lopez M, Orozco M (2012) Impact of methylation on the physical properties of DNA. Biophys J 102(9):2140–2148

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Gama-Sosa MA, Midgett RM, Slagel VA, Githens S, Kuo KC, Gehrke CW, Ehrlich M (1983) Tissue-specific differences in DNA methylation in various mammals. Biochim Biophys Acta 740(2):212–219

    Article  CAS  PubMed  Google Scholar 

  43. Song F, Smith JF, Kimura MT, Morrow AD, Matsuyama T, Nagase H, Held WA (2005) Association of tissue-specific differentially methylated regions (TDMs) with differential gene expression. Proc Natl Acad Sci U S A 102(9):3336–3341

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Bae MG, Kim JY, Choi JK (2016) Frequent hypermethylation of orphan CpG islands with enhancer activity in cancer. BMC Med Genomics 9(Suppl 1):38

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  45. Doi A, Park IH, Wen B, Murakami P, Aryee MJ, Irizarry R, Herb B, Ladd-Acosta C, Rho J, Loewer S, Miller J, Schlaeger T, Daley GQ, Feinberg AP (2009) Differential methylation of tissue- and cancer-specific CpG island shores distinguishes human induced pluripotent stem cells, embryonic stem cells and fibroblasts. Nat Genet 41(12):1350–1353

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Irizarry RA, Ladd-Acosta C, Wen B, Wu Z, Montano C, Onyango P, Cui H, Gabo K, Rongione M, Webster M, Ji H, Potash JB, Sabunciyan S, Feinberg AP (2009) The human colon cancer methylome shows similar hypo- and hypermethylation at conserved tissue-specific CpG island shores. Nat Genet 41(2):178–186

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Medvedeva YA, Khamis AM, Kulakovskiy IV, Ba-Alawi W, Bhuyan MS, Kawaji H, Lassmann T, Harbers M, Forrest AR, Bajic VB (2014) Effects of cytosine methylation on transcription factor binding sites. BMC Genomics 15:119

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  48. Wang ET, Sandberg R, Luo S, Khrebtukova I, Zhang L, Mayr C, Kingsmore SF, Schroth GP, Burge CB (2008) Alternative isoform regulation in human tissue transcriptomes. Nature 456(7221):470–476

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Mockenhaupt S, Makeyev EV (2015) Non-coding functions of alternative pre-mRNA splicing in development. Semin Cell Dev Biol 47-48:32–39

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Cooper TA, Wan L, Dreyfuss G (2009) RNA and disease. Cell 136(4):777–793

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Listerman I, Sapra AK, Neugebauer KM (2006) Cotranscriptional coupling of splicing factor recruitment and precursor messenger RNA splicing in mammalian cells. Nat Struct Mol Biol 13(9):815–822

    Article  CAS  PubMed  Google Scholar 

  52. Luco RF, Allo M, Schor IE, Kornblihtt AR, Misteli T (2011) Epigenetics in alternative pre-mRNA splicing. Cell 144(1):16–26

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Monahan K, Rudnick ND, Kehayova PD, Pauli F, Newberry KM, Myers RM, Maniatis T (2012) Role of CCCTC binding factor (CTCF) and cohesin in the generation of single-cell diversity of protocadherin-alpha gene expression. Proc Natl Acad Sci U S A 109(23):9125–9130

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Guo Y, Monahan K, Wu H, Gertz J, Varley KE, Li W, Myers RM, Maniatis T, Wu Q (2012) CTCF/cohesin-mediated DNA looping is required for protocadherin alpha promoter choice. Proc Natl Acad Sci U S A 109(51):21081–21086

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Maunakea AK, Nagarajan RP, Bilenky M, Ballinger TJ, D'Souza C, Fouse SD, Johnson BE, Hong C, Nielsen C, Zhao Y, Turecki G, Delaney A, Varhol R, Thiessen N, Shchors K, Heine VM, Rowitch DH, Xing X, Fiore C, Schillebeeckx M, Jones SJ, Haussler D, Marra MA, Hirst M, Wang T, Costello JF (2010) Conserved role of intragenic DNA methylation in regulating alternative promoters. Nature 466(7303):253–257

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Suzuki MM, Bird A (2008) DNA methylation landscapes: provocative insights from epigenomics. Nat Rev Genet 9(6):465–476

    Article  CAS  PubMed  Google Scholar 

  57. Maunakea AK, Chepelev I, Cui K, Zhao K (2013) Intragenic DNA methylation modulates alternative splicing by recruiting MeCP2 to promote exon recognition. Cell Res 23(11):1256–1269

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Ding XL, Yang X, Liang G, Wang K (2016) Isoform switching and exon skipping induced by the DNA methylation inhibitor 5-Aza-2′-deoxycytidine. Sci Rep 6:24545

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Marina RJ, Sturgill D, Bailly MA, Thenoz M, Varma G, Prigge MF, Nanan KK, Shukla S, Haque N, Oberdoerffer S (2016) TET-catalyzed oxidation of intragenic 5-methylcytosine regulates CTCF-dependent alternative splicing. EMBO J 35(3):335–355

    Article  CAS  PubMed  Google Scholar 

  60. Yearim A, Gelfman S, Shayevitch R, Melcer S, Glaich O, Mallm JP, Nissim-Rafinia M, Cohen AH, Rippe K, Meshorer E, Ast G (2015) HP1 is involved in regulating the global impact of DNA methylation on alternative splicing. Cell Rep 10(7):1122–1134

    Article  CAS  PubMed  Google Scholar 

  61. Zhang Z, Wang J, Schultz N, Zhang F, Parhad SS, Tu S, Vreven T, Zamore PD, Weng Z, Theurkauf WE (2014) The HP1 homolog rhino anchors a nuclear complex that suppresses piRNA precursor splicing. Cell 157(6):1353–1363

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Agirre E, Bellora N, Allo M, Pages A, Bertucci P, Kornblihtt AR, Eyras E (2015) A chromatin code for alternative splicing involving a putative association between CTCF and HP1alpha proteins. BMC Biol 13:31

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  63. Shukla S, Kavak E, Gregory M, Imashimizu M, Shutinoski B, Kashlev M, Oberdoerffer P, Sandberg R, Oberdoerffer S (2011) CTCF-promoted RNA polymerase II pausing links DNA methylation to splicing. Nature 479(7371):74–79

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Young JI, Hong EP, Castle JC, Crespo-Barreto J, Bowman AB, Rose MF, Kang D, Richman R, Johnson JM, Berget S, Zoghbi HY (2005) Regulation of RNA splicing by the methylation-dependent transcriptional repressor methyl-CpG binding protein 2. Proc Natl Acad Sci U S A 102(49):17551–17558

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Walsh CP, Chaillet JR, Bestor TH (1998) Transcription of IAP endogenous retroviruses is constrained by cytosine methylation. Nat Genet 20(2):116–117

    Article  CAS  PubMed  Google Scholar 

  66. Liang G, Chan MF, Tomigahara Y, Tsai YC, Gonzales FA, Li E, Laird PW, Jones PA (2002) Cooperativity between DNA methyltransferases in the maintenance methylation of repetitive elements. Mol Cell Biol 22(2):480–491

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Slotkin RK, Martienssen R (2007) Transposable elements and the epigenetic regulation of the genome. Nat Rev Genet 8(4):272–285

    Article  CAS  PubMed  Google Scholar 

  68. Xie M, Hong C, Zhang B, Lowdon RF, Xing X, Li D, Zhou X, Lee HJ, Maire CL, Ligon KL, Gascard P, Sigaroudinia M, Tlsty TD, Kadlecek T, Weiss A, O'Geen H, Farnham PJ, Madden PA, Mungall AJ, Tam A, Kamoh B, Cho S, Moore R, Hirst M, Marra MA, Costello JF, Wang T (2013) DNA hypomethylation within specific transposable element families associates with tissue-specific enhancer landscape. Nat Genet 45(7):836–841

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Reik W, Lewis A (2005) Co-evolution of X-chromosome inactivation and imprinting in mammals. Nat Rev Genet 6(5):403–410

    Article  CAS  PubMed  Google Scholar 

  70. Paulsen M, Ferguson-Smith AC (2001) DNA methylation in genomic imprinting, development, and disease. J Pathol 195(1):97–110

    Article  CAS  PubMed  Google Scholar 

  71. Kacem S, Feil R (2009) Chromatin mechanisms in genomic imprinting. Mamm Genome 20(9-10):544–556

    Article  CAS  PubMed  Google Scholar 

  72. Singmann P, Shem-Tov D, Wahl S, Grallert H, Fiorito G, Shin SY, Schramm K, Wolf P, Kunze S, Baran Y, Guarrera S, Vineis P, Krogh V, Panico S, Tumino R, Kretschmer A, Gieger C, Peters A, Prokisch H, Relton CL, Matullo G, Illig T, Waldenberger M, Halperin E (2015) Characterization of whole-genome autosomal differences of DNA methylation between men and women. Epigenetics Chromatin 8:43

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  73. Li E, Beard C, Jaenisch R (1993) Role for DNA methylation in genomic imprinting. Nature 366(6453):362–365

    Article  CAS  PubMed  Google Scholar 

  74. Du M, Zhou W, Beatty LG, Weksberg R, Sadowski PD (2004) The KCNQ1OT1 promoter, a key regulator of genomic imprinting in human chromosome 11p15.5. Genomics 84(2):288–300

    Article  CAS  PubMed  Google Scholar 

  75. Mohammad F, Pandey GK, Mondal T, Enroth S, Redrup L, Gyllensten U, Kanduri C (2012) Long noncoding RNA-mediated maintenance of DNA methylation and transcriptional gene silencing. Development 139(15):2792–2803

    Article  CAS  PubMed  Google Scholar 

  76. Lister R, Mukamel EA, Nery JR, Urich M, Puddifoot CA, Johnson ND, Lucero J, Huang Y, Dwork AJ, Schultz MD, Yu M, Tonti-Filippini J, Heyn H, Hu S, Wu JC, Rao A, Esteller M, He C, Haghighi FG, Sejnowski TJ, Behrens MM, Ecker JR (2013) Global epigenomic reconfiguration during mammalian brain development. Science 341(6146):1237905

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  77. Cotton AM, Lam L, Affleck JG, Wilson IM, Penaherrera MS, McFadden DE, Kobor MS, Lam WL, Robinson WP, Brown CJ (2011) Chromosome-wide DNA methylation analysis predicts human tissue-specific X inactivation. Hum Genet 130(2):187–201

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Murakami K, Ohhira T, Oshiro E, Qi D, Oshimura M, Kugoh H (2009) Identification of the chromatin regions coated by non-coding Xist RNA. Cytogenet Genome Res 125(1):19–25

    Article  CAS  PubMed  Google Scholar 

  79. Brown CJ, Ballabio A, Rupert JL, Lafreniere RG, Grompe M, Tonlorenzi R, Willard HF (1991) A gene from the region of the human X inactivation centre is expressed exclusively from the inactive X chromosome. Nature 349(6304):38–44

    Article  CAS  PubMed  Google Scholar 

  80. Csankovszki G, Nagy A, Jaenisch R (2001) Synergism of Xist RNA, DNA methylation, and histone hypoacetylation in maintaining X chromosome inactivation. J Cell Biol 153(4):773–784

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Navarro P, Page DR, Avner P, Rougeulle C (2006) Tsix-mediated epigenetic switch of a CTCF-flanked region of the Xist promoter determines the Xist transcription program. Genes Dev 20(20):2787–2792

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Chureau C, Chantalat S, Romito A, Galvani A, Duret L, Avner P, Rougeulle C (2011) Ftx is a non-coding RNA which affects Xist expression and chromatin structure within the X-inactivation center region. Hum Mol Genet 20(4):705–718

    Article  CAS  PubMed  Google Scholar 

  83. Barr H, Hermann A, Berger J, Tsai HH, Adie K, Prokhortchouk A, Hendrich B, Bird A (2007) Mbd2 contributes to DNA methylation-directed repression of the Xist gene. Mol Cell Biol 27(10):3750–3757

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Jin B, Ernst J, Tiedemann RL, Xu H, Sureshchandra S, Kellis M, Dalton S, Liu C, Choi JH, Robertson KD (2012) Linking DNA methyltransferases to epigenetic marks and nucleosome structure genome-wide in human tumor cells. Cell Rep 2(5):1411–1424

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Okano M, Bell DW, Haber DA, Li E (1999) DNA methyltransferases Dnmt3a and Dnmt3b are essential for de novo methylation and mammalian development. Cell 99(3):247–257

    Article  CAS  PubMed  Google Scholar 

  86. El Gazzar M, Yoza BK, Chen X, Hu J, Hawkins GA, McCall CE (2008) G9a and HP1 couple histone and DNA methylation to TNFalpha transcription silencing during endotoxin tolerance. J Biol Chem 283(47):32198–32208

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  87. Song J, Teplova M, Ishibe-Murakami S, Patel DJ (2012) Structure-based mechanistic insights into DNMT1-mediated maintenance DNA methylation. Science 335(6069):709–712

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Pathania R, Ramachandran S, Elangovan S, Padia R, Yang P, Cinghu S, Veeranan-Karmegam R, Arjunan P, Gnana-Prakasam JP, Sadanand F, Pei L, Chang CS, Choi JH, Shi H, Manicassamy S, Prasad PD, Sharma S, Ganapathy V, Jothi R, Thangaraju M (2015) DNMT1 is essential for mammary and cancer stem cell maintenance and tumorigenesis. Nat Commun 6:6910

    Article  CAS  PubMed  Google Scholar 

  89. Li E, Bestor TH, Jaenisch R (1992) Targeted mutation of the DNA methyltransferase gene results in embryonic lethality. Cell 69(6):915–926

    Article  CAS  PubMed  Google Scholar 

  90. Song CX, He C (2013) Potential functional roles of DNA demethylation intermediates. Trends Biochem Sci 38(10):480–484

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Guibert S, Weber M (2013) Functions of DNA methylation and hydroxymethylation in mammalian development. Curr Top Dev Biol 104:47–83

    Article  CAS  PubMed  Google Scholar 

  92. Pastor WA, Aravind L, Rao A (2013) TETonic shift: biological roles of TET proteins in DNA demethylation and transcription. Nat Rev Mol Cell Biol 14(6):341–356

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Williams K, Christensen J, Helin K (2011) DNA methylation: TET proteins-guardians of CpG islands? EMBO Rep 13(1):28–35

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  94. Lorsbach RB, Moore J, Mathew S, Raimondi SC, Mukatira ST, Downing JR (2003) TET1, a member of a novel protein family, is fused to MLL in acute myeloid leukemia containing the t(10,11)(q22;q23). Leukemia 17(3):637–641

    Article  CAS  PubMed  Google Scholar 

  95. Tefferi A, Levine RL, Lim KH, Abdel-Wahab O, Lasho TL, Patel J, Finke CM, Mullally A, Li CY, Pardanani A, Gilliland DG (2009) Frequent TET2 mutations in systemic mastocytosis: clinical, KITD816V and FIP1L1-PDGFRA correlates. Leukemia 23(5):900–904

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Abdel-Wahab O, Mullally A, Hedvat C, Garcia-Manero G, Patel J, Wadleigh M, Malinge S, Yao J, Kilpivaara O, Bhat R, Huberman K, Thomas S, Dolgalev I, Heguy A, Paietta E, Le Beau MM, Beran M, Tallman MS, Ebert BL, Kantarjian HM, Stone RM, Gilliland DG, Crispino JD, Levine RL (2009) Genetic characterization of TET1, TET2, and TET3 alterations in myeloid malignancies. Blood 114(1):144–147

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Koh KP, Yabuuchi A, Rao S, Huang Y, Cunniff K, Nardone J, Laiho A, Tahiliani M, Sommer CA, Mostoslavsky G, Lahesmaa R, Orkin SH, Rodig SJ, Daley GQ, Rao A (2011) Tet1 and Tet2 regulate 5-hydroxymethylcytosine production and cell lineage specification in mouse embryonic stem cells. Cell Stem Cell 8(2):200–213

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Walter J (2011) An epigenetic Tet a Tet with pluripotency. Cell Stem Cell 8(2):121–122

    Article  CAS  PubMed  Google Scholar 

  99. Wang T, Pan Q, Lin L, Szulwach KE, Song CX, He C, Wu H, Warren ST, Jin P, Duan R, Li X (2012) Genome-wide DNA hydroxymethylation changes are associated with neurodevelopmental genes in the developing human cerebellum. Hum Mol Genet 21(26):5500–5510

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Greco CM, Kunderfranco P, Rubino M, Larcher V, Carullo P, Anselmo A, Kurz K, Carell T, Angius A, Latronico MV, Papait R, Condorelli G (2016) DNA hydroxymethylation controls cardiomyocyte gene expression in development and hypertrophy. Nat Commun 7:12418

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Qin S, Li Q, Zhou J, Liu ZJ, Su N, Wilson J, Lu ZM, Deng D (2014) Homeostatic maintenance of allele-specific p16 methylation in cancer cells accompanied by dynamic focal methylation and hydroxymethylation. PLoS One 9(5):e97785

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  102. Tampe B, Tampe D, Muller CA, Sugimoto H, LeBleu V, Xu X, Muller GA, Zeisberg EM, Kalluri R, Zeisberg M (2014) Tet3-mediated hydroxymethylation of epigenetically silenced genes contributes to bone morphogenic protein 7-induced reversal of kidney fibrosis. J Am Soc Nephrol 25(5):905–912

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Xu X, Tan X, Tampe B, Nyamsuren G, Liu X, Maier LS, Sossalla S, Kalluri R, Zeisberg M, Hasenfuss G, Zeisberg EM (2015) Epigenetic balance of aberrant Rasal1 promoter methylation and hydroxymethylation regulates cardiac fibrosis. Cardiovasc Res 105(3):279–291

    Article  CAS  PubMed  Google Scholar 

  104. Tammen SA, Park LK, Dolnikowski GG, Ausman LM, Friso S, Choi SW (2015) Hepatic DNA hydroxymethylation is site-specifically altered by chronic alcohol consumption and aging. Eur J Nutr 56(2):535–544

    Article  PubMed  CAS  Google Scholar 

  105. Lister R, Ecker JR (2009) Finding the fifth base: genome-wide sequencing of cytosine methylation. Genome Res 19(6):959–966

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Lister R, Pelizzola M, Dowen RH, Hawkins RD, Hon G, Tonti-Filippini J, Nery JR, Lee L, Ye Z, Ngo QM, Edsall L, Antosiewicz-Bourget J, Stewart R, Ruotti V, Millar AH, Thomson JA, Ren B, Ecker JR (2009) Human DNA methylomes at base resolution show widespread epigenomic differences. Nature 462(7271):315–322

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Guo JU, Su Y, Shin JH, Shin J, Li H, Xie B, Zhong C, Hu S, Le T, Fan G, Zhu H, Chang Q, Gao Y, Ming GL, Song H (2014) Distribution, recognition and regulation of non-CpG methylation in the adult mammalian brain. Nat Neurosci 17(2):215–222

    Article  CAS  PubMed  Google Scholar 

  108. Goelz SE, Vogelstein B, Hamilton SR, Feinberg AP (1985) Hypomethylation of DNA from benign and malignant human colon neoplasms. Science 228(4696):187–190

    Article  CAS  PubMed  Google Scholar 

  109. Hansen KD, Timp W, Bravo HC, Sabunciyan S, Langmead B, McDonald OG, Wen B, Wu H, Liu Y, Diep D, Briem E, Zhang K, Irizarry RA, Feinberg AP (2011) Increased methylation variation in epigenetic domains across cancer types. Nat Genet 43(8):768–775

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Issa JP (2011) Epigenetic variation and cellular Darwinism. Nat Genet 43(8):724–726

    Article  CAS  PubMed  Google Scholar 

  111. Sharma S, Kelly TK, Jones PA (2010) Epigenetics in cancer. Carcinogenesis 31(1):27–36

    Article  CAS  PubMed  Google Scholar 

  112. Heyn H, Esteller M (2012) DNA methylation profiling in the clinic: applications and challenges. Nat Rev Genet 13(10):679–692

    Article  CAS  PubMed  Google Scholar 

  113. Lin JC, Jeong S, Liang G, Takai D, Fatemi M, Tsai YC, Egger G, Gal-Yam EN, Jones PA (2007) Role of nucleosomal occupancy in the epigenetic silencing of the MLH1 CpG island. Cancer Cell 12(5):432–444

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Taberlay PC, Statham AL, Kelly TK, Clark SJ, Jones PA (2014) Reconfiguration of nucleosome-depleted regions at distal regulatory elements accompanies DNA methylation of enhancers and insulators in cancer. Genome Res 24(9):1421–1432

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Hnisz D, Abraham BJ, Lee TI, Lau A, Saint-Andre V, Sigova AA, Hoke HA, Young RA (2013) Super-enhancers in the control of cell identity and disease. Cell 155(4):934–947

    Article  CAS  PubMed  Google Scholar 

  116. Heyn H, Vidal E, Ferreira HJ, Vizoso M, Sayols S, Gomez A, Moran S, Boque-Sastre R, Guil S, Martinez-Cardus A, Lin CY, Royo R, Sanchez-Mut JV, Martinez R, Gut M, Torrents D, Orozco M, Gut I, Young RA, Esteller M (2016) Epigenomic analysis detects aberrant super-enhancer DNA methylation in human cancer. Genome Biol 17(1):11

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  117. Rideout WM III, Coetzee GA, Olumi AF, Jones PA (1990) 5-Methylcytosine as an endogenous mutagen in the human LDL receptor and p53 genes. Science 249(4974):1288–1290

    Article  CAS  PubMed  Google Scholar 

  118. Feinberg AP, Vogelstein B (1983) Hypomethylation distinguishes genes of some human cancers from their normal counterparts. Nature 301(5895):89–92

    Article  CAS  PubMed  Google Scholar 

  119. Eden A, Gaudet F, Waghmare A, Jaenisch R (2003) Chromosomal instability and tumors promoted by DNA hypomethylation. Science 300(5618):455

    Article  CAS  PubMed  Google Scholar 

  120. Gaudet F, Hodgson JG, Eden A, Jackson-Grusby L, Dausman J, Gray JW, Leonhardt H, Jaenisch R (2003) Induction of tumors in mice by genomic hypomethylation. Science 300(5618):489–492

    Article  CAS  PubMed  Google Scholar 

  121. Kaneda A, Tsukamoto T, Takamura-Enya T, Watanabe N, Kaminishi M, Sugimura T, Tatematsu M, Ushijima T (2004) Frequent hypomethylation in multiple promoter CpG islands is associated with global hypomethylation, but not with frequent promoter hypermethylation. Cancer Sci 95(1):58–64

    Article  CAS  PubMed  Google Scholar 

  122. Esteller M (2007) Cancer epigenomics: DNA methylomes and histone-modification maps. Nat Rev Genet 8(4):286–298

    Article  CAS  PubMed  Google Scholar 

  123. Badal V, Chuang LS, Tan EH, Badal S, Villa LL, Wheeler CM, Li BF, Bernard HU (2003) CpG methylation of human papillomavirus type 16 DNA in cervical cancer cell lines and in clinical specimens: genomic hypomethylation correlates with carcinogenic progression. J Virol 77(11):6227–6234

    Article  PubMed  PubMed Central  Google Scholar 

  124. Hur K, Cejas P, Feliu J, Moreno-Rubio J, Burgos E, Boland CR, Goel A (2014) Hypomethylation of long interspersed nuclear element-1 (LINE-1) leads to activation of proto-oncogenes in human colorectal cancer metastasis. Gut 63(4):635–646

    Article  CAS  PubMed  Google Scholar 

  125. Collier LS, Largaespada DA (2007) Transposable elements and the dynamic somatic genome. Genome Biol 8(Suppl 1):S5

    Article  PubMed  PubMed Central  Google Scholar 

  126. Chenais B (2015) Transposable elements in cancer and other human diseases. Curr Cancer Drug Targets 15(3):227–242

    Article  CAS  PubMed  Google Scholar 

  127. Bourc'his D, Bestor TH (2004) Meiotic catastrophe and retrotransposon reactivation in male germ cells lacking Dnmt3L. Nature 431(7004):96–99

    Article  CAS  PubMed  Google Scholar 

  128. Lee E, Iskow R, Yang L, Gokcumen O, Haseley P, Luquette LJ III, Lohr JG, Harris CC, Ding L, Wilson RK, Wheeler DA, Gibbs RA, Kucherlapati R, Lee C, Kharchenko PV, Park PJ (2012) Landscape of somatic retrotransposition in human cancers. Science 337(6097):967–971

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Carreira PE, Richardson SR, Faulkner GJ (2014) L1 retrotransposons, cancer stem cells and oncogenesis. FEBS J 281(1):63–73

    Article  CAS  PubMed  Google Scholar 

  130. Helman E, Lawrence MS, Stewart C, Sougnez C, Getz G, Meyerson M (2014) Somatic retrotransposition in human cancer revealed by whole-genome and exome sequencing. Genome Res 24(7):1053–1063

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. Hattori M, Sakamoto H, Satoh K, Yamamoto T (2001) DNA demethylase is expressed in ovarian cancers and the expression correlates with demethylation of CpG sites in the promoter region of c-erbB-2 and survivin genes. Cancer Lett 169(2):155–164

    Article  CAS  PubMed  Google Scholar 

  132. Nabilsi NH, Broaddus RR, Loose DS (2009) DNA methylation inhibits p53-mediated survivin repression. Oncogene 28(19):2046–2050

    Article  CAS  PubMed  Google Scholar 

  133. de Souza Rocha Simonini P, Breiling A, Gupta N, Malekpour M, Youns M, Omranipour R, Malekpour F, Volinia S, Croce CM, Najmabadi H, Diederichs S, Sahin O, Mayer D, Lyko F, Hoheisel JD, Riazalhosseini Y (2010) Epigenetically deregulated microRNA-375 is involved in a positive feedback loop with estrogen receptor alpha in breast cancer cells. Cancer Res 70(22):9175–9184

    Article  PubMed  CAS  Google Scholar 

  134. Kang JY, Song SH, Yun J, Jeon MS, Kim HP, Han SW, Kim TY (2015) Disruption of CTCF/cohesin-mediated high-order chromatin structures by DNA methylation downregulates PTGS2 expression. Oncogene 34(45):5677–5684

    Article  CAS  PubMed  Google Scholar 

  135. Nakayama M, Wada M, Harada T, Nagayama J, Kusaba H, Ohshima K, Kozuru M, Komatsu H, Ueda R, Kuwano M (1998) Hypomethylation status of CpG sites at the promoter region and overexpression of the human MDR1 gene in acute myeloid leukemias. Blood 92(11):4296–4307

    CAS  PubMed  Google Scholar 

  136. Hanada M, Delia D, Aiello A, Stadtmauer E, Reed JC (1993) bcl-2 gene hypomethylation and high-level expression in B-cell chronic lymphocytic leukemia. Blood 82(6):1820–1828

    CAS  PubMed  Google Scholar 

  137. Naushad SM, Prayaga A, Digumarti RR, Gottumukkala SR, Kutala VK (2012) Bcl-2/adenovirus E1B 19 kDa-interacting protein 3 (BNIP3) expression is epigenetically regulated by one-carbon metabolism in invasive duct cell carcinoma of breast. Mol Cell Biochem 361(1-2):189–195

    Article  CAS  PubMed  Google Scholar 

  138. Divyya S, Naushad SM, Murthy PV, Reddy Ch R, Kutala VK (2013) GCPII modulates oxidative stress and prostate cancer susceptibility through changes in methylation of RASSF1, BNIP3, GSTP1 and Ec-SOD. Mol Biol Rep 40(10):5541–5550

    Article  CAS  PubMed  Google Scholar 

  139. Rao X, Evans J, Chae H, Pilrose J, Kim S, Yan P, Huang RL, Lai HC, Lin H, Liu Y, Miller D, Rhee JK, Huang YW, Gu F, Gray JW, Huang TM, Nephew KP (2013) CpG island shore methylation regulates caveolin-1 expression in breast cancer. Oncogene 32(38):4519–4528

    Article  CAS  PubMed  Google Scholar 

  140. Gomez A, Karlgren M, Edler D, Bernal ML, Mkrtchian S, Ingelman-Sundberg M (2007) Expression of CYP2W1 in colon tumors: regulation by gene methylation. Pharmacogenomics 8(10):1315–1325

    Article  CAS  PubMed  Google Scholar 

  141. Rajendran G, Shanmuganandam K, Bendre A, Muzumdar D, Goel A, Shiras A (2011) Epigenetic regulation of DNA methyltransferases: DNMT1 and DNMT3B in gliomas. J Neuro-Oncol 104(2):483–494

    Article  CAS  Google Scholar 

  142. Naghitorabi M, Mohammadi Asl J, Mir Mohammad Sadeghi H, Rabbani M, Jafarian-Dehkordi A, Javanmard HS (2013) Quantitative evaluation of DNMT3B promoter methylation in breast cancer patients using differential high resolution melting analysis. Res Pharm Sci 8(3):167–175

    CAS  PubMed  PubMed Central  Google Scholar 

  143. Lee HG, Kim H, Son T, Jeong Y, Kim SU, Dong SM, Park YN, Lee JD, Lee JM, Park JH (2016) Regulation of HK2 expression through alterations in CpG methylation of the HK2 promoter during progression of hepatocellular carcinoma. Oncotarget 7(27):41798–41810

    PubMed  PubMed Central  Google Scholar 

  144. Lee PS, Teaberry VS, Bland AE, Huang Z, Whitaker RS, Baba T, Fujii S, Secord AA, Berchuck A, Murphy SK (2010) Elevated MAL expression is accompanied by promoter hypomethylation and platinum resistance in epithelial ovarian cancer. Int J Cancer 126(6):1378–1389

    CAS  PubMed  Google Scholar 

  145. He Y, Cui Y, Wang W, Gu J, Guo S, Ma K, Luo X (2011) Hypomethylation of the hsa-miR-191 locus causes high expression of hsa-mir-191 and promotes the epithelial-to-mesenchymal transition in hepatocellular carcinoma. Neoplasia 13(9):841–853

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  146. Fornari F, Milazzo M, Chieco P, Negrini M, Marasco E, Capranico G, Mantovani V, Marinello J, Sabbioni S, Callegari E, Cescon M, Ravaioli M, Croce CM, Bolondi L, Gramantieri L (2012) In hepatocellular carcinoma miR-519d is up-regulated by p53 and DNA hypomethylation and targets CDKN1A/p21, PTEN, AKT3 and TIMP2. J Pathol 227(3):275–285

    Article  CAS  PubMed  Google Scholar 

  147. Brueckner B, Stresemann C, Kuner R, Mund C, Musch T, Meister M, Sultmann H, Lyko F (2007) The human let-7a-3 locus contains an epigenetically regulated microRNA gene with oncogenic function. Cancer Res 67(4):1419–1423

    Article  CAS  PubMed  Google Scholar 

  148. Zrihan-Licht S, Weiss M, Keydar I, Wreschner DH (1995) DNA methylation status of the MUC1 gene coding for a breast-cancer-associated protein. Int J Cancer 62(3):245–251

    Article  CAS  PubMed  Google Scholar 

  149. Ye L, Li X, Kong X, Wang W, Bi Y, Hu L, Cui B, Li X, Ning G (2005) Hypomethylation in the promoter region of POMC gene correlates with ectopic overexpression in thymic carcinoids. J Endocrinol 185(2):337–343

    Article  CAS  PubMed  Google Scholar 

  150. Yoshida M, Nosaka K, Yasunaga J, Nishikata I, Morishita K, Matsuoka M (2004) Aberrant expression of the MEL1S gene identified in association with hypomethylation in adult T-cell leukemia cells. Blood 103(7):2753–2760

    Article  CAS  PubMed  Google Scholar 

  151. Tabu K, Sasai K, Kimura T, Wang L, Aoyanagi E, Kohsaka S, Tanino M, Nishihara H, Tanaka S (2008) Promoter hypomethylation regulates CD133 expression in human gliomas. Cell Res 18(10):1037–1046

    Article  CAS  PubMed  Google Scholar 

  152. Gopisetty G, Xu J, Sampath D, Colman H, Puduvalli VK (2013) Epigenetic regulation of CD133/PROM1 expression in glioma stem cells by Sp1/myc and promoter methylation. Oncogene 32(26):3119–3129

    Article  CAS  PubMed  Google Scholar 

  153. Yamada N, Noguchi S, Kumazaki M, Shinohara H, Miki K, Naoe T, Akao Y (2014) Epigenetic regulation of microRNA-128a expression contributes to the apoptosis-resistance of human T-cell leukaemia jurkat cells by modulating expression of fas-associated protein with death domain (FADD). Biochim Biophys Acta 1843(3):590–602

    Article  CAS  PubMed  Google Scholar 

  154. Jun HJ, Woolfenden S, Coven S, Lane K, Bronson R, Housman D, Charest A (2009) Epigenetic regulation of c-ROS receptor tyrosine kinase expression in malignant gliomas. Cancer Res 69(6):2180–2184

    Article  CAS  PubMed  Google Scholar 

  155. Nishigaki M, Aoyagi K, Danjoh I, Fukaya M, Yanagihara K, Sakamoto H, Yoshida T, Sasaki H (2005) Discovery of aberrant expression of R-RAS by cancer-linked DNA hypomethylation in gastric cancer using microarrays. Cancer Res 65(6):2115–2124

    Article  CAS  PubMed  Google Scholar 

  156. Fu X, Deng H, Zhao L, Li J, Zhou Y, Zhang Y (2010) Distinct expression patterns of hedgehog ligands between cultured and primary colorectal cancers are associated with aberrant methylation of their promoters. Mol Cell Biochem 337(1-2):185–192

    Article  CAS  PubMed  Google Scholar 

  157. Gupta A, Godwin AK, Vanderveer L, Lu A, Liu J (2003) Hypomethylation of the synuclein gamma gene CpG island promotes its aberrant expression in breast carcinoma and ovarian carcinoma. Cancer Res 63(3):664–673

    CAS  PubMed  Google Scholar 

  158. Czekierdowski A, Czekierdowska S, Wielgos M, Smolen A, Kaminski P, Kotarski J (2006) The role of CpG islands hypomethylation and abnormal expression of neuronal protein synuclein-gamma (SNCG) in ovarian cancer. Neuro Endocrinol Lett 27(3):381–386

    CAS  PubMed  Google Scholar 

  159. Alonso MM, Diez-Valle R, Manterola L, Rubio A, Liu D, Cortes-Santiago N, Urquiza L, Jauregi P, Lopez de Munain A, Sampron N, Aramburu A, Tejada-Solis S, Vicente C, Odero MD, Bandres E, Garcia-Foncillas J, Idoate MA, Lang FF, Fueyo J, Gomez-Manzano C (2011) Genetic and epigenetic modifications of Sox2 contribute to the invasive phenotype of malignant gliomas. PLoS One 6(11):e26740

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  160. Hatano K, Miyamoto Y, Mori M, Nimura K, Nakai Y, Nonomura N, Kaneda Y (2012) Androgen-regulated transcriptional control of sialyltransferases in prostate cancer cells. PLoS One 7(2):e31234

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  161. Wang Q, Williamson M, Bott S, Brookman-Amissah N, Freeman A, Nariculam J, Hubank MJ, Ahmed A, Masters JR (2007) Hypomethylation of WNT5A, CRIP1 and S100P in prostate cancer. Oncogene 26(45):6560–6565

    Article  CAS  PubMed  Google Scholar 

  162. Bhusari S, Yang B, Kueck J, Huang W, Jarrard DF (2011) Insulin-like growth factor-2 (IGF2) loss of imprinting marks a field defect within human prostates containing cancer. Prostate 71(15):1621–1630

    Article  CAS  PubMed  Google Scholar 

  163. Baba Y, Nosho K, Shima K, Huttenhower C, Tanaka N, Hazra A, Giovannucci EL, Fuchs CS, Ogino S (2010) Hypomethylation of the IGF2 DMR in colorectal tumors, detected by bisulfite pyrosequencing, is associated with poor prognosis. Gastroenterology 139(6):1855–1864

    Article  CAS  PubMed  Google Scholar 

  164. Ogawa O, Eccles MR, Szeto J, McNoe LA, Yun K, Maw MA, Smith PJ, Reeve AE (1993) Relaxation of insulin-like growth factor II gene imprinting implicated in Wilms' tumour. Nature 362(6422):749–751

    Article  CAS  PubMed  Google Scholar 

  165. Shetty PJ, Movva S, Pasupuleti N, Vedicherlla B, Vattam KK, Venkatasubramanian S, Ahuja YR, Hasan Q (2011) Regulation of IGF2 transcript and protein expression by altered methylation in breast cancer. J Cancer Res Clin Oncol 137(2):339–345

    Article  CAS  PubMed  Google Scholar 

  166. Anwar SL, Krech T, Hasemeier B, Schipper E, Schweitzer N, Vogel A, Kreipe H, Lehmann U (2014) Deregulation of RB1 expression by loss of imprinting in human hepatocellular carcinoma. J Pathol 233(4):392–401

    Article  CAS  PubMed  Google Scholar 

  167. Jarrard DF, Kinoshita H, Shi Y, Sandefur C, Hoff D, Meisner LF, Chang C, Herman JG, Isaacs WB, Nassif N (1998) Methylation of the androgen receptor promoter CpG island is associated with loss of androgen receptor expression in prostate cancer cells. Cancer Res 58(23):5310–5314

    CAS  PubMed  Google Scholar 

  168. Tamada H, Kitazawa R, Gohji K, Kitazawa S (2001) Epigenetic regulation of human bone morphogenetic protein 6 gene expression in prostate cancer. J Bone Miner Res 16(3):487–496

    Article  CAS  PubMed  Google Scholar 

  169. Esteller M, Silva JM, Dominguez G, Bonilla F, Matias-Guiu X, Lerma E, Bussaglia E, Prat J, Harkes IC, Repasky EA, Gabrielson E, Schutte M, Baylin SB, Herman JG (2000) Promoter hypermethylation and BRCA1 inactivation in sporadic breast and ovarian tumors. J Natl Cancer Inst 92(7):564–569

    Article  CAS  PubMed  Google Scholar 

  170. Chen K, Wang G, Peng L, Liu S, Fu X, Zhou Y, Yu H, Li A, Li J, Zhang S, Bai Y, Zhang Y (2011) CADM1/TSLC1 inactivation by promoter hypermethylation is a frequent event in colorectal carcinogenesis and correlates with late stages of the disease. Int J Cancer 128(2):266–273

    Article  CAS  PubMed  Google Scholar 

  171. Graff JR, Herman JG, Lapidus RG, Chopra H, Xu R, Jarrard DF, Isaacs WB, Pitha PM, Davidson NE, Baylin SB (1995) E-cadherin expression is silenced by DNA hypermethylation in human breast and prostate carcinomas. Cancer Res 55(22):5195–5199

    CAS  PubMed  Google Scholar 

  172. Carmona FJ, Villanueva A, Vidal A, Munoz C, Puertas S, Penin RM, Goma M, Lujambio A, Piulats JM, Mesia R, Sanchez-Cespedes M, Manos M, Condom E, Eccles SA, Esteller M (2012) Epigenetic disruption of cadherin-11 in human cancer metastasis. J Pathol 228(2):230–240

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  173. Lin YL, Gui SL, Ma JG (2015) Aberrant methylation of CDH11 predicts a poor outcome for patients with bladder cancer. Oncol Lett 10(2):647–652

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  174. Mino A, Onoda N, Yashiro M, Aya M, Fujiwara I, Kubo N, Sawada T, Ohira M, Kato Y, Hirakawa K (2006) Frequent p16 CpG island hypermethylation in primary remnant gastric cancer suggesting an independent carcinogenic pathway. Oncol Rep 15(3):615–620

    CAS  PubMed  Google Scholar 

  175. Zhang YJ, Ahsan H, Chen Y, Lunn RM, Wang LY, Chen SY, Lee PH, Chen CJ, Santella RM (2002) High frequency of promoter hypermethylation of RASSF1A and p16 and its relationship to aflatoxin B1-DNA adduct levels in human hepatocellular carcinoma. Mol Carcinog 35(2):85–92

    Article  CAS  PubMed  Google Scholar 

  176. Wang J, Sasco AJ, Fu C, Xue H, Guo G, Hua Z, Zhou Q, Jiang Q, Xu B (2008) Aberrant DNA methylation of P16, MGMT, and hMLH1 genes in combination with MTHFR C677T genetic polymorphism in esophageal squamous cell carcinoma. Cancer Epidemiol Biomark Prev 17(1):118–125

    Article  CAS  Google Scholar 

  177. Raval A, Tanner SM, Byrd JC, Angerman EB, Perko JD, Chen SS, Hackanson B, Grever MR, Lucas DM, Matkovic JJ, Lin TS, Kipps TJ, Murray F, Weisenburger D, Sanger W, Lynch J, Watson P, Jansen M, Yoshinaga Y, Rosenquist R, de Jong PJ, Coggill P, Beck S, Lynch H, de la Chapelle A, Plass C (2007) Downregulation of death-associated protein kinase 1 (DAPK1) in chronic lymphocytic leukemia. Cell 129(5):879–890

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  178. Tada Y, Wada M, Taguchi K, Mochida Y, Kinugawa N, Tsuneyoshi M, Naito S, Kuwano M (2002) The association of death-associated protein kinase hypermethylation with early recurrence in superficial bladder cancers. Cancer Res 62(14):4048–4053

    CAS  PubMed  Google Scholar 

  179. Rosas SL, Koch W, da Costa Carvalho MG, Wu L, Califano J, Westra W, Jen J, Sidransky D (2001) Promoter hypermethylation patterns of p16, O6-methylguanine-DNA-methyltransferase, and death-associated protein kinase in tumors and saliva of head and neck cancer patients. Cancer Res 61(3):939–942

    CAS  PubMed  Google Scholar 

  180. Bohne A, Schlee C, Mossner M, Thibaut J, Heesch S, Thiel E, Hofmann WK, Baldus CD (2009) Epigenetic control of differential expression of specific ERG isoforms in acute T-lymphoblastic leukemia. Leuk Res 33(6):817–822

    Article  CAS  PubMed  Google Scholar 

  181. Esteller M, Hamilton SR, Burger PC, Baylin SB, Herman JG (1999) Inactivation of the DNA repair gene O6-methylguanine-DNA methyltransferase by promoter hypermethylation is a common event in primary human neoplasia. Cancer Res 59(4):793–797

    CAS  PubMed  Google Scholar 

  182. Huang YW, Liu JC, Deatherage DE, Luo J, Mutch DG, Goodfellow PJ, Miller DS, Huang TH (2009) Epigenetic repression of microRNA-129-2 leads to overexpression of SOX4 oncogene in endometrial cancer. Cancer Res 69(23):9038–9046

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  183. Formosa A, Lena AM, Markert EK, Cortelli S, Miano R, Mauriello A, Croce N, Vandesompele J, Mestdagh P, Finazzi-Agro E, Levine AJ, Melino G, Bernardini S, Candi E (2013) DNA methylation silences miR-132 in prostate cancer. Oncogene 32(1):127–134

    Article  CAS  PubMed  Google Scholar 

  184. Li Y, Xu Z, Li B, Zhang Z, Luo H, Wang Y, Lu Z, Wu X (2014) Epigenetic silencing of miRNA-9 is correlated with promoter-proximal CpG island hypermethylation in gastric cancer in vitro and in vivo. Int J Oncol 45(6):2576–2586

    Article  CAS  PubMed  Google Scholar 

  185. Herman JG, Umar A, Polyak K, Graff JR, Ahuja N, Issa JP, Markowitz S, Willson JK, Hamilton SR, Kinzler KW, Kane MF, Kolodner RD, Vogelstein B, Kunkel TA, Baylin SB (1998) Incidence and functional consequences of hMLH1 promoter hypermethylation in colorectal carcinoma. Proc Natl Acad Sci U S A 95(12):6870–6875

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  186. Esteller M, Levine R, Baylin SB, Ellenson LH, Herman JG (1998) MLH1 promoter hypermethylation is associated with the microsatellite instability phenotype in sporadic endometrial carcinomas. Oncogene 17(18):2413–2417

    Article  CAS  PubMed  Google Scholar 

  187. Leung SY, Yuen ST, Chung LP, Chu KM, Chan AS, Ho JC (1999) hMLH1 promoter methylation and lack of hMLH1 expression in sporadic gastric carcinomas with high-frequency microsatellite instability. Cancer Res 59(1):159–164

    CAS  PubMed  Google Scholar 

  188. Berdasco M, Ropero S, Setien F, Fraga MF, Lapunzina P, Losson R, Alaminos M, Cheung NK, Rahman N, Esteller M (2009) Epigenetic inactivation of the Sotos overgrowth syndrome gene histone methyltransferase NSD1 in human neuroblastoma and glioma. Proc Natl Acad Sci U S A 106(51):21830–21835

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  189. Dammann R, Li C, Yoon JH, Chin PL, Bates S, Pfeifer GP (2000) Epigenetic inactivation of a RAS association domain family protein from the lung tumour suppressor locus 3p21.3. Nat Genet 25(3):315–319

    Article  CAS  PubMed  Google Scholar 

  190. Irimia M, Fraga MF, Sanchez-Cespedes M, Esteller M (2004) CpG island promoter hypermethylation of the Ras-effector gene NORE1A occurs in the context of a wild-type K-ras in lung cancer. Oncogene 23(53):8695–8699

    Article  CAS  PubMed  Google Scholar 

  191. Guo W, Wang C, Guo Y, Shen S, Guo X, Kuang G, Dong Z (2015) RASSF5A, a candidate tumor suppressor, is epigenetically inactivated in esophageal squamous cell carcinoma. Clin Exp Metastasis 32(1):83–98

    Article  CAS  PubMed  Google Scholar 

  192. Sakai T, Toguchida J, Ohtani N, Yandell DW, Rapaport JM, Dryja TP (1991) Allele-specific hypermethylation of the retinoblastoma tumor-suppressor gene. Am J Hum Genet 48(5):880–888

    CAS  PubMed  PubMed Central  Google Scholar 

  193. Wasserkort R, Kalmar A, Valcz G, Spisak S, Krispin M, Toth K, Tulassay Z, Sledziewski AZ, Molnar B (2013) Aberrant septin 9 DNA methylation in colorectal cancer is restricted to a single CpG island. BMC Cancer 13:398

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  194. Qi J, Zhu YQ, Luo J, Tao WH (2006) Hypermethylation and expression regulation of secreted frizzled-related protein genes in colorectal tumor. World J Gastroenterol 12(44):7113–7117

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  195. Nogales V, Reinhold WC, Varma S, Martinez-Cardus A, Moutinho C, Moran S, Heyn H, Sebio A, Barnadas A, Pommier Y, Esteller M (2016) Epigenetic inactivation of the putative DNA/RNA helicase SLFN11 in human cancer confers resistance to platinum drugs. Oncotarget 7(3):3084–3097

    Article  PubMed  Google Scholar 

  196. Takada H, Wakabayashi N, Dohi O, Yasui K, Sakakura C, Mitsufuji S, Taniwaki M, Yoshikawa T (2010) Tissue factor pathway inhibitor 2 (TFPI2) is frequently silenced by aberrant promoter hypermethylation in gastric cancer. Cancer Genet Cytogenet 197(1):16–24

    Article  CAS  PubMed  Google Scholar 

  197. Guan Z, Zhang J, Song S, Dai D (2013) Promoter methylation and expression of TIMP3 gene in gastric cancer. Diagn Pathol 8:110

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  198. Catasus L, Pons C, Munoz J, Espinosa I, Prat J (2013) Promoter hypermethylation contributes to TIMP3 down-regulation in high stage endometrioid endometrial carcinomas. Histopathology 62(4):632–641

    Article  PubMed  Google Scholar 

  199. Wajed SA, Laird PW, DeMeester TR (2001) DNA methylation: an alternative pathway to cancer. Ann Surg 234(1):10–20

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  200. Esteller M (2007) Epigenetic gene silencing in cancer: the DNA hypermethylome. Hum Mol Genet 16(Spec 1):R50–R59

    Article  CAS  PubMed  Google Scholar 

  201. Baylin SB, Herman JG (2000) DNA hypermethylation in tumorigenesis: epigenetics joins genetics. Trends Genet 16(4):168–174

    Article  CAS  PubMed  Google Scholar 

  202. Murphree AL, Benedict WF (1984) Retinoblastoma: clues to human oncogenesis. Science 223(4640):1028–1033

    Article  CAS  PubMed  Google Scholar 

  203. Zhao Y, Sun J, Zhang H, Guo S, Gu J, Wang W, Tang N, Zhou X, Yu J (2014) High-frequency aberrantly methylated targets in pancreatic adenocarcinoma identified via global DNA methylation analysis using methylCap-seq. Clin Epigenetics 6(1):18

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  204. Dudziec E, Miah S, Choudhry HM, Owen HC, Blizard S, Glover M, Hamdy FC, Catto JW (2011) Hypermethylation of CpG islands and shores around specific microRNAs and mirtrons is associated with the phenotype and presence of bladder cancer. Clin Cancer Res 17(6):1287–1296

    Article  CAS  PubMed  Google Scholar 

  205. Cuddapah S, Jothi R, Schones DE, Roh TY, Cui K, Zhao K (2009) Global analysis of the insulator binding protein CTCF in chromatin barrier regions reveals demarcation of active and repressive domains. Genome Res 19(1):24–32

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  206. Mukhopadhyay R, Yu W, Whitehead J, Xu J, Lezcano M, Pack S, Kanduri C, Kanduri M, Ginjala V, Vostrov A, Quitschke W, Chernukhin I, Klenova E, Lobanenkov V, Ohlsson R (2004) The binding sites for the chromatin insulator protein CTCF map to DNA methylation-free domains genome-wide. Genome Res 14(8):1594–1602

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  207. Wang H, Maurano MT, Qu H, Varley KE, Gertz J, Pauli F, Lee K, Canfield T, Weaver M, Sandstrom R, Thurman RE, Kaul R, Myers RM, Stamatoyannopoulos JA (2012) Widespread plasticity in CTCF occupancy linked to DNA methylation. Genome Res 22(9):1680–1688

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  208. Yan H, Tang G, Wang H, Hao L, He T, Sun X, Ting AH, Deng A, Sun S (2016) DNA methylation reactivates GAD1 expression in cancer by preventing CTCF-mediated polycomb repressive complex 2 recruitment. Oncogene 35(30):3995–4008

    Article  CAS  PubMed  Google Scholar 

  209. de Maat MF, van de Velde CJ, Umetani N, de Heer P, Putter H, van Hoesel AQ, Meijer GA, van Grieken NC, Kuppen PJ, Bilchik AJ, Tollenaar RA, Hoon DS (2007) Epigenetic silencing of cyclooxygenase-2 affects clinical outcome in gastric cancer. J Clin Oncol 25(31):4887–4894

    Article  PubMed  CAS  Google Scholar 

  210. Miremadi A, Oestergaard MZ, Pharoah PD, Caldas C (2007) Cancer genetics of epigenetic genes. Hum Mol Genet 16(Spec 1):R28–R49

    Article  CAS  PubMed  Google Scholar 

  211. Jones JS, Amos CI, Pande M, Gu X, Chen J, Campos IM, Wei Q, Rodriguez-Bigas M, Lynch PM, Frazier ML (2006) DNMT3b polymorphism and hereditary nonpolyposis colorectal cancer age of onset. Cancer Epidemiol Biomark Prev 15(5):886–891

    Article  CAS  Google Scholar 

  212. Shen H, Wang L, Spitz MR, Hong WK, Mao L, Wei Q (2002) A novel polymorphism in human cytosine DNA-methyltransferase-3B promoter is associated with an increased risk of lung cancer. Cancer Res 62(17):4992–4995

    CAS  PubMed  Google Scholar 

  213. Montgomery KG, Liu MC, Eccles DM, Campbell IG (2004) The DNMT3B C→T promoter polymorphism and risk of breast cancer in a British population: a case-control study. Breast Cancer Res 6(4):R390–R394

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  214. Singal R, Das PM, Manoharan M, Reis IM, Schlesselman JJ (2005) Polymorphisms in the DNA methyltransferase 3b gene and prostate cancer risk. Oncol Rep 14(2):569–573

    CAS  PubMed  Google Scholar 

  215. Di Croce L, Raker VA, Corsaro M, Fazi F, Fanelli M, Faretta M, Fuks F, Lo Coco F, Kouzarides T, Nervi C, Minucci S, Pelicci PG (2002) Methyltransferase recruitment and DNA hypermethylation of target promoters by an oncogenic transcription factor. Science 295(5557):1079–1082

    Article  PubMed  Google Scholar 

  216. Coutinho DF, Monte-Mor BC, Vianna DT, Rouxinol ST, Batalha AB, Bueno AP, Boulhosa AM, Fernandez TS, Pombo-de-Oliveira MS, Gutiyama LM, Abdelhay E, Zalcberg IR (2015) TET2 expression level and 5-hydroxymethylcytosine are decreased in refractory cytopenia of childhood. Leuk Res 39(10):1103–1108

    Article  CAS  PubMed  Google Scholar 

  217. Delhommeau F, Dupont S, Della Valle V, James C, Trannoy S, Masse A, Kosmider O, Le Couedic JP, Robert F, Alberdi A, Lecluse Y, Plo I, Dreyfus FJ, Marzac C, Casadevall N, Lacombe C, Romana SP, Dessen P, Soulier J, Viguie F, Fontenay M, Vainchenker W, Bernard OA (2009) Mutation in TET2 in myeloid cancers. N Engl J Med 360(22):2289–2301

    Article  PubMed  Google Scholar 

  218. Langemeijer SM, Kuiper RP, Berends M, Knops R, Aslanyan MG, Massop M, Stevens-Linders E, van Hoogen P, van Kessel AG, Raymakers RA, Kamping EJ, Verhoef GE, Verburgh E, Hagemeijer A, Vandenberghe P, de Witte T, van der Reijden BA, Jansen JH (2009) Acquired mutations in TET2 are common in myelodysplastic syndromes. Nat Genet 41(7):838–842

    Article  CAS  PubMed  Google Scholar 

  219. Haffner MC, Chaux A, Meeker AK, Esopi DM, Gerber J, Pellakuru LG, Toubaji A, Argani P, Iacobuzio-Donahue C, Nelson WG, Netto GJ, De Marzo AM, Yegnasubramanian S (2011) Global 5-hydroxymethylcytosine content is significantly reduced in tissue stem/progenitor cell compartments and in human cancers. Oncotarget 2(8):627–637

    Article  PubMed  PubMed Central  Google Scholar 

  220. Murata A, Baba Y, Ishimoto T, Miyake K, Kosumi K, Harada K, Kurashige J, Iwagami S, Sakamoto Y, Miyamoto Y, Yoshida N, Yamamoto M, Oda S, Watanabe M, Nakao M, Baba H (2015) TET family proteins and 5-hydroxymethylcytosine in esophageal squamous cell carcinoma. Oncotarget 6(27):23372–23382

    Article  PubMed  PubMed Central  Google Scholar 

  221. Udali S, Guarini P, Moruzzi S, Ruzzenente A, Tammen SA, Guglielmi A, Conci S, Pattini P, Olivieri O, Corrocher R, Choi SW, Friso S (2015) Global DNA methylation and hydroxymethylation differ in hepatocellular carcinoma and cholangiocarcinoma and relate to survival rate. Hepatology 62(2):496–504

    Article  CAS  PubMed  Google Scholar 

  222. Thienpont B, Steinbacher J, Zhao H, D'Anna F, Kuchnio A, Ploumakis A, Ghesquiere B, Van Dyck L, Boeckx B, Schoonjans L, Hermans E, Amant F, Kristensen VN, Koh KP, Mazzone M, Coleman ML, Carell T, Carmeliet P, Lambrechts D (2016) Tumour hypoxia causes DNA hypermethylation by reducing TET activity. Nature 537(7618):63–68

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  223. Kent WJ, Sugnet CW, Furey TS, Roskin KM, Pringle TH, Zahler AM, Haussler D (2002) The human genome browser at UCSC. Genome Res 12(6):996–1006

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  224. Moran S, Martinez-Cardus A, Sayols S, Musulen E, Balana C, Estival-Gonzalez A, Moutinho C, Heyn H, Diaz-Lagares A, de Moura MC, Stella GM, Comoglio PM, Ruiz-Miro M, Matias-Guiu X, Pazo-Cid R, Anton A, Lopez-Lopez R, Soler G, Longo F, Guerra I, Fernandez S, Assenov Y, Plass C, Morales R, Carles J, Bowtell D, Mileshkin L, Sia D, Tothill R, Tabernero J, Llovet JM, Esteller M (2016) Epigenetic profiling to classify cancer of unknown primary: a multicentre, retrospective analysis. Lancet Oncol 17(10):1386–1395

    Article  PubMed  Google Scholar 

  225. Esteller M, Garcia-Foncillas J, Andion E, Goodman SN, Hidalgo OF, Vanaclocha V, Baylin SB, Herman JG (2000) Inactivation of the DNA-repair gene MGMT and the clinical response of gliomas to alkylating agents. N Engl J Med 343(19):1350–1354

    Article  CAS  PubMed  Google Scholar 

  226. Hegi ME, Diserens AC, Gorlia T, Hamou MF, de Tribolet N, Weller M, Kros JM, Hainfellner JA, Mason W, Mariani L, Bromberg JE, Hau P, Mirimanoff RO, Cairncross JG, Janzer RC, Stupp R (2005) MGMT gene silencing and benefit from temozolomide in glioblastoma. N Engl J Med 352(10):997–1003

    Article  CAS  PubMed  Google Scholar 

  227. Amatu A, Sartore-Bianchi A, Moutinho C, Belotti A, Bencardino K, Chirico G, Cassingena A, Rusconi F, Esposito A, Nichelatti M, Esteller M, Siena S (2013) Promoter CpG island hypermethylation of the DNA repair enzyme MGMT predicts clinical response to dacarbazine in a phase II study for metastatic colorectal cancer. Clin Cancer Res 19(8):2265–2272

    Article  CAS  PubMed  Google Scholar 

  228. Xu Y, Diao L, Chen Y, Liu Y, Wang C, Ouyang T, Li J, Wang T, Fan Z, Fan T, Lin B, Deng D, Narod SA, Xie Y (2013) Promoter methylation of BRCA1 in triple-negative breast cancer predicts sensitivity to adjuvant chemotherapy. Ann Oncol 24(6):1498–1505

    Article  CAS  PubMed  Google Scholar 

  229. Moutinho C, Martinez-Cardus A, Santos C, Navarro-Perez V, Martinez-Balibrea E, Musulen E, Carmona FJ, Sartore-Bianchi A, Cassingena A, Siena S, Elez E, Tabernero J, Salazar R, Abad A, Esteller M (2014) Epigenetic inactivation of the BRCA1 interactor SRBC and resistance to oxaliplatin in colorectal cancer. J Natl Cancer Inst 106(1):djt322

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), Barcelona, Catalonia, Spain

    Humberto J. Ferreira & Manel Esteller

  2. Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Catalonia, Spain

    Manel Esteller

  3. Department of Physiological Sciences II, School of Medicine, University of Barcelona, Barcelona, Catalonia, Spain

    Manel Esteller

Authors
  1. Humberto J. Ferreira
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Manel Esteller
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Manel Esteller .

Editor information

Editors and Affiliations

  1. Josep Carreras Leukaemia, Research Institute, Badalona, Barcelona, Spain

    Tanya Vavouri

  2. IGTP, IMPPC, Badalona, Barcelona, Spain

    Miguel A. Peinado

Rights and permissions

Reprints and permissions

Copyright information

© 2018 Springer Science+Business Media, LLC, part of Springer Nature

About this protocol

Check for updates. Verify currency and authenticity via CrossMark

Cite this protocol

Ferreira, H.J., Esteller, M. (2018). CpG Islands in Cancer: Heads, Tails, and Sides. In: Vavouri, T., Peinado, M. (eds) CpG Islands. Methods in Molecular Biology, vol 1766. Humana Press, New York, NY. https://doi.org/10.1007/978-1-4939-7768-0_4

Download citation

  • DOI: https://doi.org/10.1007/978-1-4939-7768-0_4

  • Published:

  • Publisher Name: Humana Press, New York, NY

  • Print ISBN: 978-1-4939-7767-3

  • Online ISBN: 978-1-4939-7768-0

  • eBook Packages: Springer Protocols

Publish with us

Policies and ethics

Search

Navigation