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Proximal Regulatory Elements with Emphasis on CpG Rich Regions

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Genomic Elements in Health, Disease and Evolution

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Abstract

Transcriptional regulation in eukaryotes is a multi-step procedure which the DNA template is transcribed into RNA by RNA polymerase II in a combinatorial manner, where specific proteins (general transcription factors, activators and co-activators) are binding to regulatory elements on the DNA (core and proximal promoters, CpG islands, enhancers, silencers, locus control regions). More than 50 % of the mammalian genes initiate transcription from short regions in DNA that contains high frequency of CpG sites referred to as CpG islands. CpG islands are generally non-methylated and associated with the majority of gene promoters. Many studies have identified examples of CpG island methylation in CpG promoters that lead to abnormal gene silencing in cancer cells. CpG island methylation is also function in X-inactivation and genomic imprinting. Differential CpG island methylation is also shown in embryonic stem cells but also in somatic cells indicating their role in gene expression during cellular differentiation and cell type determination. CpG islands, therefore illustrate the complex role played by DNA methylation in the regulation of transcription.

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References

  1. Grummt I (1999) Regulation of mammalian ribosomal gene transcription by RNA polymerase I. Prog Nucleic Acid Res Mol Biol 62:109–154

    Article  CAS  PubMed  Google Scholar 

  2. Willis IM (1993) RNA polymerase III. Genes, factors and transcriptional specificity. Eur J Biochem 212:1–11

    Article  CAS  PubMed  Google Scholar 

  3. Sims RJ 3rd, Mandal SS, Reinberg D (2004) Recent highlights of RNA-polymerase-II-mediated transcription. Curr Opin Cell Biol 16:263–271

    Article  CAS  PubMed  Google Scholar 

  4. Herr AJ, Jensen MB, Dalmay T, Baulcombe DC (2005) RNA polymerase IV directs silencing of endogenous DNA. Science 308:118–120

    Article  CAS  PubMed  Google Scholar 

  5. Wierzbicki AT, Ream TS, Haag JR, Pikaard CS (2009) RNA polymerase V transcription guides ARGONAUTE4 to chromatin. Nat Genet 41:630–634

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  6. Thomas MC, Chiang CM (2006) The general transcription machinery and general cofactors. Crit Rev Biochem Mol Biol 41:105–178

    Article  CAS  PubMed  Google Scholar 

  7. He Y, Fang J, Taatjes DJ, Nogales E (2013) Structural visualization of key steps in human transcription initiation. Nature 495:481–486

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  8. Holstege FC, Fiedler U, Timmers HT (1997) Three transitions in the RNA polymerase II transcription complex during initiation. EMBO J 16:7468–7480

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  9. Hampsey M (1998) Molecular genetics of the RNA polymerase II general transcriptional machinery. Microbiol Mol Biol Rev 62:465–503

    PubMed Central  CAS  PubMed  Google Scholar 

  10. Karin M (1990) Too many transcription factors: positive and negative interactions. New Biol 2:126–131

    CAS  PubMed  Google Scholar 

  11. Ptashne M, Gann A (1997) Transcriptional activation by recruitment. Nature 386:569–577

    Article  CAS  PubMed  Google Scholar 

  12. Pabo CO, Sauer RT (1992) Transcription factors: structural families and principles of DNA recognition. Annu Rev Biochem 61:1053–1095

    Article  CAS  PubMed  Google Scholar 

  13. Rosenfeld MG, Lunyak VV, Glass CK (2006) Sensors and signals: a coactivator/corepressor/epigenetic code for integrating signal-dependent programs of transcriptional response. Genes Dev 20:1405–1428

    Article  CAS  PubMed  Google Scholar 

  14. Spiegelman BM, Heinrich R (2004) Biological control through regulated transcriptional coactivators. Cell 119:157–167

    Article  CAS  PubMed  Google Scholar 

  15. Capuano F, Mulleder M, Kok R, Blom HJ, Ralser M (2014) Cytosine DNA methylation is found in Drosophila melanogaster but absent in Saccharomyces cerevisiae, Schizosaccharomyces pombe, and other yeast species. Anal Chem 86:3697–3702

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  16. Jaenisch R, Bird A (2003) Epigenetic regulation of gene expression: how the genome integrates intrinsic and environmental signals. Nat Genet 33 Suppl:245–254

    Google Scholar 

  17. Robertson KD, Uzvolgyi E, Liang G, Talmadge C, Sumegi J, Gonzales FA, Jones PA (1999) The human DNA methyltransferases (DNMTs) 1, 3a and 3b: coordinate mRNA expression in normal tissues and overexpression in tumors. Nucleic Acids Res 27:2291–2298

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  18. Chahwan R, Wontakal SN, Roa S (2010) Crosstalk between genetic and epigenetic information through cytosine deamination. Trends Genet 26:443–448

    Article  CAS  PubMed  Google Scholar 

  19. Bird A, Taggart M, Frommer M, Miller OJ, Macleod D (1985) A fraction of the mouse genome that is derived from islands of nonmethylated, CpG-rich DNA. Cell 40:91–99

    Article  CAS  PubMed  Google Scholar 

  20. Illingworth RS, Gruenewald-Schneider U, Webb S, Kerr AR, James KD, Turner DJ, Smith C, Harrison DJ, Andrews R, Bird AP (2010) Orphan CpG islands identify numerous conserved promoters in the mammalian genome. PLoS Genet 6:e1001134

    Article  PubMed Central  PubMed  Google Scholar 

  21. Tazi J, Bird A (1990) Alternative chromatin structure at CpG islands. Cell 60:909–920

    Article  CAS  PubMed  Google Scholar 

  22. Blackledge NP, Klose R (2011) CpG island chromatin: a platform for gene regulation. Epigenetics 6:147–152

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  23. Antequera F, Bird A (1993) Number of CpG islands and genes in human and mouse. Proc Natl Acad Sci U S A 90:11995–11999

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  24. Gardiner-Garden M, Frommer M (1994) Transcripts and CpG islands associated with the pro-opiomelanocortin gene and other neurally expressed genes. J Mol Endocrinol 12:365–382

    Article  CAS  PubMed  Google Scholar 

  25. 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 103:1412–1417

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  26. 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 466:253–257

    Article  PubMed Central  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  28. Larsen F, Gundersen G, Lopez R, Prydz H (1992) CpG islands as gene markers in the human genome. Genomics 13:1095–1107

    Article  CAS  PubMed  Google Scholar 

  29. Antequera F, Macleod D, Bird AP (1989) Specific protection of methylated CpGs in mammalian nuclei. Cell 58:509–517

    Article  CAS  PubMed  Google Scholar 

  30. Gilbert SL, Sharp PA (1999) Promoter-specific hypoacetylation of X-inactivated genes. Proc Natl Acad Sci U S A 96:13825–13830

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  31. Antequera F, Boyes J, Bird A (1990) High levels of de novo methylation and altered chromatin structure at CpG islands in cell lines. Cell 62:503–514

    Article  CAS  PubMed  Google Scholar 

  32. Esteller M (2002) CpG island hypermethylation and tumor suppressor genes: a booming present, a brighter future. Oncogene 21:5427–5440

    Article  CAS  PubMed  Google Scholar 

  33. Nan X, Ng HH, Johnson CA, Laherty CD, Turner BM, Eisenman RN, Bird A (1998) Transcriptional repression by the methyl-CpG-binding protein MeCP2 involves a histone deacetylase complex. Nature 393:386–389

    Article  CAS  PubMed  Google Scholar 

  34. Wade PA (2001) Methyl CpG-binding proteins and transcriptional repression. Bioessays 23:1131–1137

    Article  CAS  PubMed  Google Scholar 

  35. Weih F, Nitsch D, Reik A, Schutz G, Becker PB (1991) Analysis of CpG methylation and genomic footprinting at the tyrosine aminotransferase gene: DNA methylation alone is not sufficient to prevent protein binding in vivo. EMBO J 10:2559–2567

    PubMed Central  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  38. Adachi N, Lieber MR (2002) Bidirectional gene organization: a common architectural feature of the human genome. Cell 109:807–809

    Article  CAS  PubMed  Google Scholar 

  39. Somma MP, Pisano C, Lavia P (1991) The housekeeping promoter from the mouse CpG island HTF9 contains multiple protein-binding elements that are functionally redundant. Nucleic Acids Res 19:2817–2824

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  40. Ladenburger EM, Keller C, Knippers R (2002) Identification of a binding region for human origin recognition complex proteins 1 and 2 that coincides with an origin of DNA replication. Mol Cell Biol 22:1036–1048

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  41. Cuadrado M, Sacristan M, Antequera F (2001) Species-specific organization of CpG island promoters at mammalian homologous genes. EMBO Rep 2:586–592

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  42. Antequera F (2003) Structure, function and evolution of CpG island promoters. Cell Mol Life Sci 60:1647–1658

    Article  CAS  PubMed  Google Scholar 

  43. Mouse Genome Sequencing, Waterston RH, Lindblad-Toh K, Birney E, Rogers J, Abril JF, Agarwal P, Agarwala R, Ainscough R, Alexandersson M, An P, Antonarakis SE, Attwood J, Baertsch R, Bailey J, Barlow K, Beck S, Berry E, Birren B, Bloom T, Bork P, Botcherby M, Bray N, Brent MR, Brown DG, Brown SD, Bult C, Burton J, Butler J, Campbell RD, Carninci P, Cawley S, Chiaromonte F, Chinwalla AT, Church DM, Clamp M, Clee C, Collins FS, Cook LL, Copley RR, Coulson A, Couronne O, Cuff J, Curwen V, Cutts T, Daly M, David R, Davies J, Delehaunty KD, Deri J, Dermitzakis ET, Dewey C, Dickens NJ, Diekhans M, Dodge S, Dubchak I, Dunn DM, Eddy SR, Elnitski L, Emes RD, Eswara P, Eyras E, Felsenfeld A, Fewell GA, Flicek P, Foley K, Frankel WN, Fulton LA, Fulton RS, Furey TS, Gage D, Gibbs RA, Glusman G, Gnerre S, Goldman N, Goodstadt L, Grafham D, Graves TA, Green ED, Gregory S, Guigo R, Guyer M, Hardison RC, Haussler D, Hayashizaki Y, Hillier LW, Hinrichs A, Hlavina W, Holzer T, Hsu F, Hua A, Hubbard T, Hunt A, Jackson I, Jaffe DB, Johnson LS, Jones M, Jones TA, Joy A, Kamal M et al (2002) Initial sequencing and comparative analysis of the mouse genome. Nature 420:520–562

    Article  Google Scholar 

  44. Antequera F, Bird A (1999) CpG islands as genomic footprints of promoters that are associated with replication origins. Curr Biol 9:R661–R667

    Article  CAS  PubMed  Google Scholar 

  45. Cooper DN, Taggart MH, Bird AP (1983) Unmethylated domains in vertebrate DNA. Nucleic Acids Res 11:647–658

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  46. Reik W (2007) Stability and flexibility of epigenetic gene regulation in mammalian development. Nature 447:425–432

    Article  CAS  PubMed  Google Scholar 

  47. Edwards CA, Ferguson-Smith AC (2007) Mechanisms regulating imprinted genes in clusters. Curr Opin Cell Biol 19:281–289

    Article  CAS  PubMed  Google Scholar 

  48. Weber M, Hellmann I, Stadler MB, Ramos L, Paabo S, Rebhan M, Schubeler D (2007) Distribution, silencing potential and evolutionary impact of promoter DNA methylation in the human genome. Nat Genet 39:457–466

    Article  CAS  PubMed  Google Scholar 

  49. Eckhardt F, Lewin J, Cortese R, Rakyan VK, Attwood J, Burger M, Burton J, Cox TV, Davies R, Down TA, Haefliger C, Horton R, Howe K, Jackson DK, Kunde J, Koenig C, Liddle J, Niblett D, Otto T, Pettett R, Seemann S, Thompson C, West T, Rogers J, Olek A, Berlin K, Beck S (2006) DNA methylation profiling of human chromosomes 6, 20 and 22. Nat Genet 38:1378–1385

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  50. Jiang T, Xing B, Rao J (2008) Recent developments of biological reporter technology for detecting gene expression. Biotechnol Genet Eng Rev 25:41–75

    Article  CAS  PubMed  Google Scholar 

  51. Brenowitz M, Senear DF, Shea MA, Ackers GK (1986) Quantitative DNase footprint titration: a method for studying protein-DNA interactions. Methods Enzymol 130:132–181

    Article  CAS  PubMed  Google Scholar 

  52. Galas DJ, Schmitz A (1978) DNAse footprinting: a simple method for the detection of protein-DNA binding specificity. Nucleic Acids Res 5:3157–3170

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  53. Crawford GE, Holt IE, Whittle J, Webb BD, Tai D, Davis S, Margulies EH, Chen Y, Bernat JA, Ginsburg D, Zhou D, Luo S, Vasicek TJ, Daly MJ, Wolfsberg TG, Collins FS (2006) Genome-wide mapping of DNase hypersensitive sites using massively parallel signature sequencing (MPSS). Genome Res 16:123–131

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  54. Kumar V, Muratani M, Rayan NA, Kraus P, Lufkin T, Ng HH, Prabhakar S (2013) Uniform, optimal signal processing of mapped deep-sequencing data. Nat Biotechnol 31:615–622

    Article  CAS  PubMed  Google Scholar 

  55. Collas P (2010) The current state of chromatin immunoprecipitation. Mol Biotechnol 45:87–100

    Article  CAS  PubMed  Google Scholar 

  56. Elgar G, Vavouri T (2008) Tuning in to the signals: noncoding sequence conservation in vertebrate genomes. Trends Genet 24:344–352

    Article  CAS  PubMed  Google Scholar 

  57. Narlikar L, Ovcharenko I (2009) Identifying regulatory elements in eukaryotic genomes. Brief Funct Genomic Proteomic 8:215–230

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  58. Wingender E, Chen X, Fricke E, Geffers R, Hehl R, Liebich I, Krull M, Matys V, Michael H, Ohnhauser R, Pruss M, Schacherer F, Thiele S, Urbach S (2001) The TRANSFAC system on gene expression regulation. Nucleic Acids Res 29:281–283

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  59. Sandelin A, Alkema W, Engstrom P, Wasserman WW, Lenhard B (2004) JASPAR: an open-access database for eukaryotic transcription factor binding profiles. Nucleic Acids Res 32:D91–D94

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  60. Siepel A, Bejerano G, Pedersen JS, Hinrichs AS, Hou M, Rosenbloom K, Clawson H, Spieth J, Hillier LW, Richards S, Weinstock GM, Wilson RK, Gibbs RA, Kent WJ, Miller W, Haussler D (2005) Evolutionarily conserved elements in vertebrate, insect, worm, and yeast genomes. Genome Res 15:1034–1050

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  61. Blanchette M, Tompa M (2003) FootPrinter: a program designed for phylogenetic footprinting. Nucleic Acids Res 31:3840–3842

    Article  PubMed Central  CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Molecular Genetics Thalassaemia Department, The Cyprus Institute of Neurology and Genetics, 6 International Airport Avenue, Ayios Dhometios, 2370, Nicosia, Cyprus

    Pavlos Fanis B.Sc., Ph.D.

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  1. Pavlos Fanis B.Sc., Ph.D.
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Correspondence to Pavlos Fanis B.Sc., Ph.D. .

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  1. Department of Life and Health Sciences and University of Nicosia Medical School, University of Nicosia, Nicosia, Cyprus

    Kyriacos Felekkis

  2. Department of Biological Sciences, Molecular Medicine Research Center, University of Cyprus, Nicosia, Cyprus

    Konstantinos Voskarides

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Fanis, P. (2015). Proximal Regulatory Elements with Emphasis on CpG Rich Regions. In: Felekkis, K., Voskarides, K. (eds) Genomic Elements in Health, Disease and Evolution. Springer, New York, NY. https://doi.org/10.1007/978-1-4939-3070-8_11

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