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Cellular and Molecular Life Sciences

, Volume 72, Issue 21, pp 4095–4109 | Cite as

Genetic and epigenetic trends in telomere research: a novel way in immunoepigenetics

  • Dora Melicher
  • Edit I. Buzas
  • Andras FalusEmail author
Review

Abstract

Telomeres are protective heterochromatic structures that cap the end of linear chromosomes and play a key role in preserving genomic stability. Telomere length represents a balance between processes that shorten telomeres during cell divisions with incomplete DNA replication and the ones that lengthen telomeres by the action of telomerase, an RNA–protein complex with reverse transcriptase activity which adds telomeric repeats to DNA molecule ends. Telomerase activity and telomere length have a crucial role in cellular ageing and in the pathobiology of several human diseases attracting intense research. The last few decades have witnessed remarkable advances in our understanding about telomeres, telomere-associated proteins, and the biogenesis and regulation of the telomerase holoenzyme complex, as well as about telomerase activation and the telomere-independent functions of telomerase. Emerging data have revealed that telomere length can be modified by genetic and epigenetic factors, sex hormones, reactive oxygen species and inflammatory reactions. It has become clear that, in order to find out more about the factors influencing the rate of telomere attrition in vivo, it is crucial to explore both genetic and epigenetic mechanisms. Since the telomere/telomerase assembly is under the control of multiple epigenetic influences, the unique design of twin studies could help disentangle genetic and environmental factors in the functioning of the telomere/telomerase system. It is surprising that the literature on twin studies investigating this topic is rather scarce. This review aims to provide an overview of some important immune response- and epigenetics-related aspects of the telomere/telomerase system demanding more research, while presenting the available twin data published in connection with telomere research so far. By emphasising what we know and what we still do not know in these areas, another purpose of this review is to urge more twin studies in telomere research.

Keywords

Telomere length Telomerase Twin epigenetics Immune cells In vitro Telomere twin studies Epigenetic regulation 

References

  1. 1.
    Blackburn EH (2001) Switching and signaling at the telomere. Cell 106(6):661–673PubMedCrossRefGoogle Scholar
  2. 2.
    van Steensel B, Smogorzewska A, de Lange T (1998) TRF2 protects human telomeres from end-to-end fusions. Cell 92(3):401–413PubMedCrossRefGoogle Scholar
  3. 3.
    de Lange T (2005) Shelterin: the protein complex that shapes and safeguards human telomeres. Genes Dev 19(18):2100–2110PubMedCrossRefGoogle Scholar
  4. 4.
    Blasco MA (2007) The epigenetic regulation of mammalian telomeres. Nat Rev Genet 8(4):299–309PubMedCrossRefGoogle Scholar
  5. 5.
    Griffith JD et al (1999) Mammalian telomeres end in a large duplex loop. Cell 97(4):503–514PubMedCrossRefGoogle Scholar
  6. 6.
    Palm W, de Lange T (2008) How shelterin protects mammalian telomeres. Annu Rev Genet 42:301–334PubMedCrossRefGoogle Scholar
  7. 7.
    Cesare AJ, Reddel RR (2010) Alternative lengthening of telomeres: models, mechanisms and implications. Nat Rev Genet 11(5):319–330PubMedCrossRefGoogle Scholar
  8. 8.
    Hockemeyer D et al (2006) Recent expansion of the telomeric complex in rodents: two distinct POT1 proteins protect mouse telomeres. Cell 126(1):63–77PubMedCrossRefGoogle Scholar
  9. 9.
    Chan SW, Blackburn EH (2002) New ways not to make ends meet: telomerase. DNA damage proteins and heterochromatin. Oncogene 21(4):553–563PubMedCrossRefGoogle Scholar
  10. 10.
    Collins K, Mitchell JR (2002) Telomerase in the human organism. Oncogene 21(4):564–579PubMedCrossRefGoogle Scholar
  11. 11.
    Cohen SB et al (2007) Protein composition of catalytically active human telomerase from immortal cells. Science 315(5820):1850–1853PubMedCrossRefGoogle Scholar
  12. 12.
    Venteicher AS et al (2009) A human telomerase holoenzyme protein required for Cajal body localization and telomere synthesis. Science 323(5914):644–648PubMedCentralPubMedCrossRefGoogle Scholar
  13. 13.
    Kim NW et al (1994) Specific association of human telomerase activity with immortal cells and cancer. Science 266(5193):2011–2015PubMedCrossRefGoogle Scholar
  14. 14.
    Wright WE et al (1996) Telomerase activity in human germline and embryonic tissues and cells. Dev Genet 18(2):173–179PubMedCrossRefGoogle Scholar
  15. 15.
    Morrison SJ et al (1996) Telomerase activity in hematopoietic cells is associated with self-renewal potential. Immunity 5(3):207–216PubMedCrossRefGoogle Scholar
  16. 16.
    Blackburn EH, Greider CW, Szostak JW (2006) Telomeres and telomerase: the path from maize, Tetrahymena and yeast to human cancer and aging. Nat Med 12(10):1133–1138PubMedCrossRefGoogle Scholar
  17. 17.
    Hathcock KS, Jeffrey Y, Hodes RJ (2005) In vivo regulation of telomerase activity and telomere length. Immunol Rev 205:104–113PubMedCrossRefGoogle Scholar
  18. 18.
    Blasco MA (2005) Telomeres and human disease: ageing, cancer and beyond. Nat Rev Genet 6(8):611–622PubMedCrossRefGoogle Scholar
  19. 19.
    Lansdorp PM (2009) Telomeres and disease. EMBO J 28(17):2532–2540PubMedCentralPubMedCrossRefGoogle Scholar
  20. 20.
    Mitchell JR, Wood E, Collins K (1999) A telomerase component is defective in the human disease dyskeratosis congenita. Nature 402(6761):551–555PubMedCrossRefGoogle Scholar
  21. 21.
    Calado RT, Young NS (2009) Telomere diseases. N Engl J Med 361(24):2353–2365PubMedCentralPubMedCrossRefGoogle Scholar
  22. 22.
    Aubert G, Lansdorp PM (2008) Telomeres and aging. Physiol Rev 88(2):557–579PubMedCrossRefGoogle Scholar
  23. 23.
    Walne AJ et al (2007) Genetic heterogeneity in autosomal recessive dyskeratosis congenita with one subtype due to mutations in the telomerase-associated protein NOP10. Hum Mol Genet 16(13):1619–1629PubMedCentralPubMedCrossRefGoogle Scholar
  24. 24.
    Savage SA et al (2008) TINF2, a component of the shelterin telomere protection complex, is mutated in dyskeratosis congenita. Am J Hum Genet 82(2):501–509PubMedCentralPubMedCrossRefGoogle Scholar
  25. 25.
    Vulliamy T et al (2008) Mutations in the telomerase component NHP2 cause the premature ageing syndrome dyskeratosis congenita. Proc Natl Acad Sci USA 105(23):8073–8078PubMedCentralPubMedCrossRefGoogle Scholar
  26. 26.
    Yamaguchi H et al (2003) Mutations of the human telomerase RNA gene (TERC) in aplastic anemia and myelodysplastic syndrome. Blood 102(3):916–918PubMedCrossRefGoogle Scholar
  27. 27.
    Marrone A et al (2004) Heterozygous telomerase RNA mutations found in dyskeratosis congenita and aplastic anemia reduce telomerase activity via haploinsufficiency. Blood 104(13):3936–3942PubMedCrossRefGoogle Scholar
  28. 28.
    Ly H et al (2005) Functional characterization of telomerase RNA variants found in patients with hematologic disorders. Blood 105(6):2332–2339PubMedCrossRefGoogle Scholar
  29. 29.
    Vulliamy TJ et al (2005) Mutations in the reverse transcriptase component of telomerase (TERT) in patients with bone marrow failure. Blood Cells Mol Dis 34(3):257–263PubMedCrossRefGoogle Scholar
  30. 30.
    Armanios MY et al (2007) Telomerase mutations in families with idiopathic pulmonary fibrosis. N Engl J Med 356(13):1317–1326PubMedCrossRefGoogle Scholar
  31. 31.
    Qazilbash MH et al (1997) A new syndrome of familial aplastic anemia and chronic liver disease. Acta Haematol 97(3):164–167PubMedCrossRefGoogle Scholar
  32. 32.
    Carulli L, Anzivino C (2014) Telomere and telomerase in chronic liver disease and hepatocarcinoma. World J Gastroenterol 20(20):6287–6292PubMedCentralPubMedCrossRefGoogle Scholar
  33. 33.
    Calado RT et al (2009) A spectrum of severe familial liver disorders associate with telomerase mutations. PLoS ONE 4(11):e7926PubMedCentralPubMedCrossRefGoogle Scholar
  34. 34.
    Satoh M et al (2009) Effect of intensive lipid-lowering therapy on telomere erosion in endothelial progenitor cells obtained from patients with coronary artery disease. Clin Sci 116(11–12):827–835PubMedCrossRefGoogle Scholar
  35. 35.
    Fitzpatrick AL et al (2007) Leukocyte telomere length and cardiovascular disease in the cardiovascular health study. Am J Epidemiol 165(1):14–21PubMedCrossRefGoogle Scholar
  36. 36.
    Farzaneh-Far R et al (2008) Prognostic value of leukocyte telomere length in patients with stable coronary artery disease—data from the heart and soul study. Arterioscler Thromb Vasc Biol 28(7):1379–1384PubMedCentralPubMedCrossRefGoogle Scholar
  37. 37.
    Wang YY et al (2011) Association of shorter mean telomere length with large artery stiffness in patients with coronary heart disease. Aging Male 14(1):27–32PubMedCrossRefGoogle Scholar
  38. 38.
    Epel ES et al (2009) The rate of leukocyte telomere shortening predicts mortality from cardiovascular disease in elderly men. Aging (Albany NY) 1(1):81–88Google Scholar
  39. 39.
    Salpea KD, Humphries SE (2010) Telomere length in atherosclerosis and diabetes. Atherosclerosis 209(1):35–38PubMedCentralPubMedCrossRefGoogle Scholar
  40. 40.
    Salpea KD et al (2010) Association of telomere length with type 2 diabetes, oxidative stress and UCP2 gene variation. Atherosclerosis 209(1):42–50PubMedCentralPubMedCrossRefGoogle Scholar
  41. 41.
    Al-Attas OS et al (2010) Adiposity and insulin resistance correlate with telomere length in middle-aged Arabs: the influence of circulating adiponectin. Eur J Endocrinol 163(4):601–607PubMedCentralPubMedCrossRefGoogle Scholar
  42. 42.
    Cao Y, Bryan TM, Reddel RR (2008) Increased copy number of the TERT and TERC telomerase subunit genes in cancer cells. Cancer Sci 99(6):1092–1099PubMedCrossRefGoogle Scholar
  43. 43.
    Shay JW, Wright WE (2011) Role of telomeres and telomerase in cancer. Semin Cancer Biol 21(6):349–353PubMedCentralPubMedCrossRefGoogle Scholar
  44. 44.
    Londono-Vallejo JA (2008) Telomere instability and cancer. Biochimie 90(1):73–82PubMedCrossRefGoogle Scholar
  45. 45.
    Bryan TM et al (1997) Evidence for an alternative mechanism for maintaining telomere length in human tumors and tumor-derived cell lines. Nat Med 3(11):1271–1274PubMedCrossRefGoogle Scholar
  46. 46.
    Bryan TM et al (1995) Telomere elongation in immortal human-cells without detectable telomerase activity. EMBO J 14(17):4240–4248PubMedCentralPubMedGoogle Scholar
  47. 47.
    Dunham MA et al (2000) Telomere maintenance by recombination in human cells. Nat Genet 26(4):447–450PubMedCrossRefGoogle Scholar
  48. 48.
    O’Sullivan RJ, Almouzni G (2014) Assembly of telomeric chromatin to create alternative endings. Trends Cell Biol 24(11):675–685PubMedCrossRefGoogle Scholar
  49. 49.
    Murnane JP et al (1994) Telomere dynamics in an immortal human cell-line. EMBO J 13(20):4953–4962PubMedCentralPubMedGoogle Scholar
  50. 50.
    Natarajan S, McEachern MJ (2002) Recombinational telomere elongation promoted by DNA circles. Mol Cell Biol 22(13):4512–4521PubMedCrossRefGoogle Scholar
  51. 51.
    Arora R et al (2014) RNaseH1 regulates TERRA-telomeric DNA hybrids and telomere maintenance in ALT tumour cells. Nat Commun 5:5220PubMedCentralPubMedCrossRefGoogle Scholar
  52. 52.
    Balk B et al (2013) Telomeric RNA-DNA hybrids affect telomere-length dynamics and senescence. Nat Struct Mol Biol 20(10):1199–1205PubMedCrossRefGoogle Scholar
  53. 53.
    Cusanelli E, Chartrand P (2015) Telomeric repeat-containing RNA TERRA: a noncoding RNA connecting telomere biology to genome integrity. Front Genet 6:143PubMedCentralPubMedCrossRefGoogle Scholar
  54. 54.
    Gibbons RJ et al (2000) Mutations in ATRX, encoding a SWI/SNF-like protein, cause diverse changes in the pattern of DNA methylation. Nat Genet 24(4):368–371PubMedCrossRefGoogle Scholar
  55. 55.
    Lewis PW et al (2010) Daxx is an H3.3-specific histone chaperone and cooperates with ATRX in replication-independent chromatin assembly at telomeres. Proc Natl Acad Sci USA 107(32):14075–14080PubMedCentralPubMedCrossRefGoogle Scholar
  56. 56.
    Drane P et al (2010) The death-associated protein DAXX is a novel histone chaperone involved in the replication-independent deposition of H3.3. Genes Dev 24(12):1253–1265PubMedCentralPubMedCrossRefGoogle Scholar
  57. 57.
    Schoeftner S, Blasco MA (2009) A ‘higher order’ of telomere regulation: telomere heterochromatin and telomeric RNAs. EMBO J 28(16):2323–2336PubMedCentralPubMedCrossRefGoogle Scholar
  58. 58.
    Benetti R, Garcia-Cao M, Blasco MA (2007) Telomere length regulates the epigenetic status of mammalian telomeres and subtelomeres. Nat Genet 39(2):243–250PubMedCrossRefGoogle Scholar
  59. 59.
    Hu J et al (2012) Antitelomerase therapy provokes ALT and mitochondrial adaptive mechanisms in cancer. Cell 148(4):651–663PubMedCentralPubMedCrossRefGoogle Scholar
  60. 60.
    van Dongen J et al (2012) The continuing value of twin studies in the omics era. Nat Rev Genet 13(9):640–653PubMedCrossRefGoogle Scholar
  61. 61.
    Bell JT, Saffery R (2012) The value of twins in epigenetic epidemiology. Int J Epidemiol 41(1):140–150PubMedCrossRefGoogle Scholar
  62. 62.
    Heath AC, Jardine R, Martin NG (1989) Interactive effects of genotype and social environment on alcohol consumption in female twins. J Stud Alcohol 50(1):38–48PubMedCrossRefGoogle Scholar
  63. 63.
    Bell JT, Spector TD (2011) A twin approach to unraveling epigenetics. Trends Genet 27(3):116–125PubMedCentralPubMedCrossRefGoogle Scholar
  64. 64.
    Tan Q et al (2013) Twins for epigenetic studies of human aging and development. Ageing Res Rev 12(1):182–187PubMedCentralPubMedCrossRefGoogle Scholar
  65. 65.
    Kaszubowska L (2008) Telomere shortening and ageing of the immune system. J Physiol Pharmacol 59(Suppl 9):169–186PubMedGoogle Scholar
  66. 66.
    Slagboom PE, Droog S, Boomsma DI (1994) Genetic determination of telomere size in humans: a twin study of three age groups. Am J Hum Genet 55(5):876–882PubMedCentralPubMedGoogle Scholar
  67. 67.
    Lange K, Weeks D, Boehnke M (1988) Programs for pedigree analysis—Mendel, Fisher, and Dgene. Genet Epidemiol 5(6):471–472PubMedCrossRefGoogle Scholar
  68. 68.
    Kosciolek BA, Rowley PT (1998) Human lymphocyte telomerase is genetically regulated. Genes Chromosom Cancer 21(2):124–130PubMedCrossRefGoogle Scholar
  69. 69.
    Jeanclos E et al (2000) Telomere length inversely correlates with pulse pressure and is highly familial. Hypertension 36(2):195–200PubMedCrossRefGoogle Scholar
  70. 70.
    Bischoff C et al (2005) The heritability of telomere length among the elderly and oldest-old. Twin Res Hum Genet 8(5):433–439PubMedCrossRefGoogle Scholar
  71. 71.
    Bischoff C et al (2005) Telomere length among the elderly and oldest-old. Twin Res Hum Genet 8(5):425–432PubMedCrossRefGoogle Scholar
  72. 72.
    Vogler GP (1993) Methodology for genetic-studies of twins and families—Neale, Mc, Cardon, Lr. Behav Genet 23(1):107–108CrossRefGoogle Scholar
  73. 73.
    Broer L et al (2013) Meta-analysis of telomere length in 19,713 subjects reveals high heritability, stronger maternal inheritance and a paternal age effect. Eur J Hum Genet 21(10):1163–1168PubMedCentralPubMedCrossRefGoogle Scholar
  74. 74.
    Cawthon RM et al (2003) Association between telomere length in blood and mortality in people aged 60 years or older. Lancet 361(9355):393–395PubMedCrossRefGoogle Scholar
  75. 75.
    Honig LS et al (2006) Shorter telomeres are associated with mortality in those with APOE epsilon4 and dementia. Ann Neurol 60(2):181–187PubMedCrossRefGoogle Scholar
  76. 76.
    Bakaysa SL et al (2007) Telomere length predicts survival independent of genetic influences. Aging Cell 6(6):769–774PubMedCrossRefGoogle Scholar
  77. 77.
    Kimura M et al (2008) Telomere length and mortality: a study of leukocytes in elderly Danish twins. Am J Epidemiol 167(7):799–806PubMedCentralPubMedCrossRefGoogle Scholar
  78. 78.
    Deelen J et al (2014) Leukocyte telomere length associates with prospective mortality independent of immune-related parameters and known genetic markers. Int J Epidemiol 43(3):878–886PubMedCentralPubMedCrossRefGoogle Scholar
  79. 79.
    Martin-Ruiz CM et al (2005) Telomere length in white blood cells is not associated with morbidity or mortality in the oldest old: a population-based study. Aging Cell 4(6):287–290PubMedCrossRefGoogle Scholar
  80. 80.
    Bischoff C et al (2006) No association between telomere length and survival among the elderly and oldest old. Epidemiology 17(2):190–194PubMedCrossRefGoogle Scholar
  81. 81.
    Harris SE et al (2006) The association between telomere length, physical health, cognitive ageing, and mortality in non-demented older people. Neurosci Lett 406(3):260–264PubMedCrossRefGoogle Scholar
  82. 82.
    Huda N et al (2007) Shared environmental factors associated with telomere length maintenance in elderly male twins. Aging Cell 6(5):709–713PubMedCrossRefGoogle Scholar
  83. 83.
    Rufer N et al (1999) Telomere fluorescence measurements in granulocytes and T lymphocyte subsets point to a high turnover of hematopoietic stem cells and memory T cells in early childhood. J Exp Med 190(2):157–167PubMedCentralPubMedCrossRefGoogle Scholar
  84. 84.
    Nawrot TS et al (2004) Telomere length and possible link to X chromosome. Lancet 363(9408):507–510PubMedCrossRefGoogle Scholar
  85. 85.
    Andrew T et al (2006) Mapping genetic loci that determine leukocyte telomere length in a large sample of unselected female sibling pairs. Am J Hum Genet 78(3):480–486PubMedCentralPubMedCrossRefGoogle Scholar
  86. 86.
    Cherkas LF et al (2008) The association between physical activity in leisure time and leukocyte telomere length. Arch Intern Med 168(2):154–158PubMedCrossRefGoogle Scholar
  87. 87.
    Hjelmborg JB et al (2015) The heritability of leucocyte telomere length dynamics. J Med Genet 52(5):297–302PubMedCentralPubMedCrossRefGoogle Scholar
  88. 88.
    Okuda K et al (2002) Telomere length in the newborn. Pediatr Res 52(3):377–381PubMedCrossRefGoogle Scholar
  89. 89.
    Akkad A et al (2006) Telomere length in small-for-gestational-age babies. BJOG 113(3):318–323PubMedCrossRefGoogle Scholar
  90. 90.
    Benetos A et al (2014) Sex difference in leukocyte telomere length is ablated in opposite-sex co-twins. Int J Epidemiol 43(6):1799–1805PubMedCentralPubMedCrossRefGoogle Scholar
  91. 91.
    Graakjaer J et al (2004) The relative lengths of individual telomeres are defined in the zygote and strictly maintained during life. Aging Cell 3(3):97–102PubMedCrossRefGoogle Scholar
  92. 92.
    Levy D et al (2010) Genome-wide association identifies OBFC1 as a locus involved in human leukocyte telomere biology. Proc Natl Acad Sci USA 107(20):9293–9298PubMedCentralPubMedCrossRefGoogle Scholar
  93. 93.
    Codd V et al (2010) Common variants near TERC are associated with mean telomere length. Nat Genet 42(3):197–199PubMedCentralPubMedCrossRefGoogle Scholar
  94. 94.
    Mangino M et al (2012) Genome-wide meta-analysis points to CTC1 and ZNF676 as genes regulating telomere homeostasis in humans. Hum Mol Genet 21(24):5385–5394PubMedCentralPubMedCrossRefGoogle Scholar
  95. 95.
    Codd V et al (2013) Identification of seven loci affecting mean telomere length and their association with disease. Nat Genet 45(4):422–427PubMedCentralPubMedCrossRefGoogle Scholar
  96. 96.
    Takubo K et al (2002) Telomere lengths are characteristic in each human individual. Exp Gerontol 37(4):523–531PubMedCrossRefGoogle Scholar
  97. 97.
    Hunt SC et al (2008) Leukocyte telomeres are longer in African Americans than in whites: the National Heart, Lung, and Blood Institute Family Heart Study and the Bogalusa Heart Study. Aging Cell 7(4):451–458PubMedCentralPubMedCrossRefGoogle Scholar
  98. 98.
    Kim S et al (2012) Association between genetic variants in DNA and histone methylation and telomere length. Plos ONE 7(7):e40504Google Scholar
  99. 99.
    Atzmon G et al (2010) Genetic variation in human telomerase is associated with telomere length in Ashkenazi centenarians. Proc Natl Acad Sci USA 107:1710–1717PubMedCentralPubMedCrossRefGoogle Scholar
  100. 100.
    Vasa-Nicotera M et al (2005) Mapping of a major locus that determines telomere length in humans. Am J Hum Genet 76(1):147–151PubMedCentralPubMedCrossRefGoogle Scholar
  101. 101.
    Weng N-P (2008) Telomere and adaptive immunity. Mech Ageing Dev 129(1–2):60–66PubMedCentralPubMedCrossRefGoogle Scholar
  102. 102.
    Weng NP et al (1997) Tales of tails: regulation of telomere length and telomerase activity during lymphocyte development, differentiation, activation, and aging. Immunol Rev 160:43–54PubMedCrossRefGoogle Scholar
  103. 103.
    Son NH et al (2000) Lineage-specific telomere shortening and unaltered capacity for telomerase expression in human T and B lymphocytes with age. J Immunol 165(3):1191–1196PubMedCrossRefGoogle Scholar
  104. 104.
    Lin J et al (2010) Analyses and comparisons of telomerase activity and telomere length in human T and B cells: insights for epidemiology of telomere maintenance. J Immunol Methods 352(1–2):71–80PubMedCentralPubMedCrossRefGoogle Scholar
  105. 105.
    Wolf D et al (2006) Telomere length of in vivo expanded CD4(+)CD25 (+) regulatory T-cells is preserved in cancer patients. Cancer Immunol Immunother 55(10):1198–1208PubMedCrossRefGoogle Scholar
  106. 106.
    Broccoli D, Young JW, Delange T (1995) Telomerase activity in normal and malignant hematopoietic-Cells. Proc Natl Acad Sci USA 92(20):9082–9086PubMedCentralPubMedCrossRefGoogle Scholar
  107. 107.
    Xu D et al (1996) Supression of telomerase activity in HL60 cells after treatment with differentiating agents. Leukemia 10(8):1354–1357PubMedGoogle Scholar
  108. 108.
    Bestilny LJ et al (1996) Selective inhibition of telomerase activity during terminal differentiation of immortal cell lines. Cancer Res 56(16):3796–3802PubMedGoogle Scholar
  109. 109.
    Savoysky E et al (1996) Down-regulation of telomerase activity is an early event in the differentiation of HL60 cells. Biochem Biophys Res Commun 226(2):329–334PubMedCrossRefGoogle Scholar
  110. 110.
    Holt SE, Wright WE, Shay JW (1996) Regulation of telomerase activity in immortal cell lines. Mol Cell Biol 16(6):2932–2939PubMedCentralPubMedCrossRefGoogle Scholar
  111. 111.
    Sharma HW et al (1996) Telomeres, telomerase and cancer: Is the magic bullet real? Anticancer Res 16(1):511–515PubMedGoogle Scholar
  112. 112.
    Weng N (2001) Interplay between telomere length and telomerase in human leukocyte differentiation and aging. J Leukoc Biol 70(6):861–867PubMedGoogle Scholar
  113. 113.
    Chaves-Dias C et al (2001) Induction of telomerase activity during development of human mast cells from peripheral blood CD34+ cells: comparisons with tumor mast-cell lines. J Immunol 166(11):6647–6656PubMedCrossRefGoogle Scholar
  114. 114.
    Blasco MA et al (1996) Differential regulation of telomerase activity and telomerase RNA during multi-stage tumorigenesis. Nat Genet 12(2):200–204PubMedCrossRefGoogle Scholar
  115. 115.
    Nakamura TM et al (1997) Telomerase catalytic subunit homologs from fission yeast and human. Science 277(5328):955–959PubMedCrossRefGoogle Scholar
  116. 116.
    Buchkovich KJ, Greider CW (1996) Telomerase regulation during entry into the cell cycle in normal human T cells. Mol Biol Cell 7(9):1443–1454PubMedCentralPubMedCrossRefGoogle Scholar
  117. 117.
    Liu KB et al (1999) Constitutive and regulated expression of telomerase reverse transcriptase (hTERT) in human lymphocytes. Proc Natl Acad Sci USA 96(9):5147–5152PubMedCentralPubMedCrossRefGoogle Scholar
  118. 118.
    Antonio Moro-Garcia M, Alonso-Arias R, Lopez-Larrea C (2012) Molecular Mechanisms Involved in the Aging of the T-cell Immune Response. Curr Genom 13(8):589–602CrossRefGoogle Scholar
  119. 119.
    Macallan DC et al (2004) Rapid turnover of effector-memory CD4(+) T cells in healthy humans. J Exp Med 200(2):255–260PubMedCentralPubMedCrossRefGoogle Scholar
  120. 120.
    Plunkett FJ et al (2005) The impact of telomere erosion on memory CD8+ T cells in patients with X-linked lymphoproliferative syndrome. Mech Ageing Dev 126(8):855–865PubMedCrossRefGoogle Scholar
  121. 121.
    Fletcher JM et al (2005) Cytomegalovirus-specific CD4(+) T cells in healthy carriers are continuously driven to replicative exhaustion. J Immunol 175(12):8218–8225PubMedCrossRefGoogle Scholar
  122. 122.
    Fritsch RD et al (2005) Stepwise differentiation of CD4 memory T cells defined by expression of CCR7 and CD27. J Immunol 175(10):6489–6497PubMedCrossRefGoogle Scholar
  123. 123.
    Akbar AN, Vukmanovic-Stejic M (2007) Telomerase in T lymphocytes: use it and lose it? J Immunol 178(11):6689–6694PubMedCrossRefGoogle Scholar
  124. 124.
    Deville L, Hillion J, Segal-Bendirdjian E (2009) Telomerase regulation in hematological cancers: a matter of stemness? Biochim Et Biophys Acta Mol Basis Dis 1792(4):229–239CrossRefGoogle Scholar
  125. 125.
    Liu K, Hodes RJ, Weng N (2001) Cutting edge: telomerase activation in human T lymphocytes does not require increase in telomerase reverse transcriptase (hTERT) protein but is associated with hTERT phosphorylation and nuclear translocation. J Immunol 166(8):4826–4830PubMedCrossRefGoogle Scholar
  126. 126.
    Kang SS et al (1999) Akt protein kinase enhances human telomerase activity through phosphorylation of telomerase reverse transcriptase subunit. J Biol Chem 274(19):13085–13090PubMedCrossRefGoogle Scholar
  127. 127.
    Smith LL, Coller HA, Roberts JM (2003) Telomerase modulates expression of growth-controlling genes and enhances cell proliferation. Nat Cell Biol 5(5):474–479PubMedCrossRefGoogle Scholar
  128. 128.
    Li S et al (2005) Cellular and gene expression responses involved in the rapid growth inhibition of human cancer cells by RNA interference-mediated depletion of telomerase RNA. J Biol Chem 280(25):23709–23717PubMedCrossRefGoogle Scholar
  129. 129.
    Bagheri S et al (2006) Genes and pathways downstream of telomerase in melanoma metastasis. Proc Natl Acad Sci USA 103(30):11306–11311PubMedCentralPubMedCrossRefGoogle Scholar
  130. 130.
    Park JI et al (2009) Telomerase modulates Wnt signalling by association with target gene chromatin. Nature 460(7251):66–72PubMedCentralPubMedCrossRefGoogle Scholar
  131. 131.
    Maida Y et al (2009) An RNA-dependent RNA polymerase formed by TERT and the RMRP RNA. Nature 461(7261):230–235PubMedCentralPubMedCrossRefGoogle Scholar
  132. 132.
    Hoffmeyer K et al (2012) Wnt/β-catenin signaling regulates telomerase in stem cells and cancer cells. Science 336(6088):1549–1554PubMedCrossRefGoogle Scholar
  133. 133.
    Santos JH et al (2004) Mitochondrial hTERT exacerbates free-radical-mediated mtDNA damage. Aging Cell 3(6):399–411PubMedCrossRefGoogle Scholar
  134. 134.
    Santos JH, Meyer JN, Van Houten B (2006) Mitochondrial localization of telomerase as a determinant for hydrogen peroxide-induced mitochondrial DNA damage and apoptosis. Hum Mol Genet 15(11):1757–1768PubMedCrossRefGoogle Scholar
  135. 135.
    Haendeler J et al (2003) Hydrogen peroxide triggers nuclear export of telomerase reverse transcriptase via Src kinase family-dependent phosphorylation of tyrosine 707. Mol Cell Biol 23(13):4598–4610PubMedCentralPubMedCrossRefGoogle Scholar
  136. 136.
    Ahmed S et al (2008) Telomerase does not counteract telomere shortening but protects mitochondrial function under oxidative stress. J Cell Sci 121(Pt 7):1046–1053PubMedCrossRefGoogle Scholar
  137. 137.
    Haendeler J et al (2009) Mitochondrial telomerase reverse transcriptase binds to and protects mitochondrial DNA and function from damage. Arterioscler Thromb Vasc Biol 29(6):929–935PubMedCrossRefGoogle Scholar
  138. 138.
    Saretzki G (2009) Telomerase, mitochondria and oxidative stress. Exp Gerontol 44(8):485–492PubMedCrossRefGoogle Scholar
  139. 139.
    Indran IR, Hande MP, Pervaiz S (2011) hTERT overexpression alleviates intracellular ROS production, improves mitochondrial function, and inhibits ROS-mediated apoptosis in cancer cells. Cancer Res 71(1):266–276PubMedCrossRefGoogle Scholar
  140. 140.
    Sharma NK et al (2012) Human telomerase acts as a hTR-independent reverse transcriptase in mitochondria. Nucleic Acids Res 40(2):712–725PubMedCentralPubMedCrossRefGoogle Scholar
  141. 141.
    Singhapol C et al (2013) Mitochondrial telomerase protects cancer cells from nuclear DNA damage and apoptosis. Plos ONE 8(1):e52989Google Scholar
  142. 142.
    Sahin E et al (2011) Telomere dysfunction induces metabolic and mitochondrial compromise. Nature 470(7334):359–365PubMedCentralPubMedCrossRefGoogle Scholar
  143. 143.
    Kim JH et al (2013) The relationship between leukocyte mitochondrial DNA copy number and telomere length in Community-Dwelling elderly women. Plos ONE 8(6):e67227Google Scholar
  144. 144.
    Lopatina NG et al (2003) Control mechanisms in the regulation of telomerase reverse transcriptase expression in differentiating human teratocarcinoma cells. Biochem Biophys Res Commun 306(3):650–659PubMedCrossRefGoogle Scholar
  145. 145.
    Shin KH et al (2003) Hypermethylation of the hTERT promoter inhibits the expression of telomerase activity in normal oral fibroblasts and senescent normal oral keratinocytes. Br J Cancer 89(8):1473–1478PubMedCentralPubMedCrossRefGoogle Scholar
  146. 146.
    Zinn RL et al (2007) hTERT is expressed in cancer cell lines despite promoter DNA methylation by preservation of unmethylated DNA and active chromatin around the transcription start site. Cancer Res 67(1):194–201PubMedCrossRefGoogle Scholar
  147. 147.
    Dessain SK et al (2000) Methylation of the human telomerase gene CpG island. Cancer Res 60(3):537–541PubMedGoogle Scholar
  148. 148.
    Devereux TR et al (1999) DNA methylation analysis of the promoter region of the human telomerase reverse transcriptase (hTERT) gene. Cancer Res 59(24):6087–6090PubMedGoogle Scholar
  149. 149.
    Kumari A et al (2009) Positive regulation of human telomerase reverse transcriptase gene expression and telomerase activity by DNA methylation in pancreatic cancer. Ann Surg Oncol 16(4):1051–1059PubMedCrossRefGoogle Scholar
  150. 150.
    Kumari A, Srinivasan R, Wig JD (2009) Effect of c-MYC and E2F1 gene silencing and of 5-azacytidine treatment on telomerase activity in pancreatic cancer-derived cell lines. Pancreatology 9(4):360–368PubMedCrossRefGoogle Scholar
  151. 151.
    Guilleret I et al (2002) Hypermethylation of the human telomerase catalytic subunit (hTERT) gene correlates with telomerase activity. Int J Cancer 101(4):335–341PubMedCrossRefGoogle Scholar
  152. 152.
    Takakura M et al (2001) Telomerase activation by histone deacetylase inhibitor in normal cells. Nucleic Acids Res 29(14):3006–3011PubMedCentralPubMedCrossRefGoogle Scholar
  153. 153.
    Hou M et al (2002) The histone deacetylase inhibitor trichostatin a derepresses the telomerase reverse transcriptase (hTERT) gene in human cells. Exp Cell Res 274(1):25–34PubMedCrossRefGoogle Scholar
  154. 154.
    Murakami J et al (2005) Effects of histone deacetylase inhibitor FR901228 on the expression level of telomerase reverse transcriptase in oral cancer. Cancer Chemother Pharmacol 56(1):22–28PubMedCrossRefGoogle Scholar
  155. 155.
    Zhu K et al (2008) Telomerase expression and cell proliferation in ovarian cancer cells induced by histone deacetylase inhibitors. Arch Gynecol Obstet 277(1):15–19PubMedCrossRefGoogle Scholar
  156. 156.
    Khaw AK et al (2007) Inhibition of telomerase activity and human telomerase reverse transcriptase gene expression by histone deacetylase inhibitor in human brain cancer cells. Mutat Res 625(1–2):134–144PubMedCrossRefGoogle Scholar
  157. 157.
    Atkinson SP et al (2005) Lack of telomerase gene expression in alternative lengthening of telomere cells is associated with chromatin remodeling of the hTR and hTERT gene promoters. Cancer Res 65(17):7585–7590PubMedGoogle Scholar
  158. 158.
    Sui X et al (2013) Epigenetic regulation of the human telomerase reverse transciptase gene: a potential therapeutic target for the treatment of leukemia (review). Oncol Lett 6(2):317–322PubMedCentralPubMedGoogle Scholar
  159. 159.
    Garcia-Cao M et al (2004) Epigenetic regulation of telomere length in mammalian cells by the Suv39h1 and Suv39h2 histone methyltransferases. Nat Genet 36(1):94–99PubMedCrossRefGoogle Scholar
  160. 160.
    Gonzalo S et al (2006) DNA methyltransferases control telomere length and telomere recombination in mammalian cells. Nat Cell Biol 8(4):416–424PubMedCrossRefGoogle Scholar
  161. 161.
    Scheuring UJ, Sabzevari H, Theofilopoulos AN (2002) Proliferative arrest and cell cycle regulation in CD8(+)CD28(-) versus CD8(+)CD28(+) T cells. Hum Immunol 63(11):1000–1009PubMedCrossRefGoogle Scholar
  162. 162.
    Bellon M et al (2010) HTLV-I Tax-dependent and -independent events associated with immortalization of human primary T lymphocytes. Blood 115(12):2441–2448PubMedCentralPubMedCrossRefGoogle Scholar
  163. 163.
    Lu QJ et al (2003) DNA methylation and chromatin structure regulate T cell perforin gene expression. J Immunol 170(10):5124–5132PubMedCrossRefGoogle Scholar
  164. 164.
    Liu Y et al (2009) DNA methylation inhibition increases T cell KIR expression through effects on both promoter methylation and transcription factors. Clin Immunol 130(2):213–224PubMedCentralPubMedCrossRefGoogle Scholar
  165. 165.
    Chen YX et al (2010) Decreased ERK and JNK signaling contribute to gene overexpression in “senescent” CD4+ CD28-T cells through epigenetic mechanisms. J Leukoc Biol 87(1):137–145PubMedCentralPubMedCrossRefGoogle Scholar
  166. 166.
    Gonzalo S et al (2005) Role of the RB1 family in stabilizing histone methylation at constitutive heterochromatin. Nat Cell Biol 7(4):420–428PubMedCrossRefGoogle Scholar
  167. 167.
    Garcia-Cao M et al (2002) A role for the Rb family of proteins in controlling telomere length. Nat Genet 32(3):415–419PubMedCrossRefGoogle Scholar
  168. 168.
    Makarov VL et al (1993) Nucleosomal organization of telomere-specific chromatin in rat. Cell 73(4):775–787PubMedCrossRefGoogle Scholar
  169. 169.
    Tommerup H, Dousmanis A, Delange T (1994) Unusual chromatin in human telomeres. Mol Cell Biol 14(9):5777–5785PubMedCentralPubMedCrossRefGoogle Scholar
  170. 170.
    Baur JA et al (2001) Telomere position effect in human cells. Science 292(5524):2075–2077PubMedCrossRefGoogle Scholar
  171. 171.
    Koering CE et al (2002) Human telomeric position effect is determined by chromosomal context and telomeric chromatin integrity. EMBO Rep 3(11):1055–1061PubMedCentralPubMedCrossRefGoogle Scholar
  172. 172.
    Samper E, Flores JA, Blasco MA (2001) Restoration of telomerase activity rescues chromosomal instability and premature aging in Terc(−/−) mice with short telomeres. EMBO Rep 2(9):800–807PubMedCentralPubMedCrossRefGoogle Scholar
  173. 173.
    Hemann MT et al (2001) The shortest telomere, not average telomere length, is critical for cell viability and chromosome stability. Cell 107(1):67–77PubMedCrossRefGoogle Scholar
  174. 174.
    Azzalin CM et al (2007) Telomeric repeat containing RNA and RNA surveillance factors at mammalian chromosome ends. Science 318(5851):798–801PubMedCrossRefGoogle Scholar
  175. 175.
    Schoeftner S, Blasco MA (2008) Developmentally regulated transcription of mammalian telomeres by DNA-dependent RNA polymerase II. Nat Cell Biol 10(2):228–236PubMedCrossRefGoogle Scholar
  176. 176.
    Nergadze SG et al (2009) CpG-island promoters drive transcription of human telomeres. RNA 15(12):2186–2194PubMedCentralPubMedCrossRefGoogle Scholar
  177. 177.
    Redon S, Reichenbach P, Lingner J (2010) The non-coding RNA TERRA is a natural ligand and direct inhibitor of human telomerase. Nucleic Acids Res 38(17):5797–5806PubMedCentralPubMedCrossRefGoogle Scholar
  178. 178.
    Meyerson M et al (1997) hEST2, the putative human telomerase catalytic subunit gene, is up-regulated in tumor cells and during immortalization. Cell 90(4):785–795PubMedCrossRefGoogle Scholar
  179. 179.
    Bodnar AG et al (1998) Extension of life-span by introduction of telomerase into normal human cells. Science 279(5349):349–352PubMedCrossRefGoogle Scholar
  180. 180.
    Horikawa I et al (1999) Cloning and characterization of the promoter region of human telomerase reverse transcriptase gene. Cancer Res 59(4):826–830PubMedGoogle Scholar
  181. 181.
    Ulaner GA et al (1998) Telomerase activity in human development is regulated by human telomerase reverse transcriptase (hTERT) transcription and by alternate splicing of hTERT transcripts. Cancer Res 58(18):4168–4172PubMedGoogle Scholar
  182. 182.
    Ulaner GA et al (2000) Regulation of telomerase by alternate splicing of human telomerase reverse transcriptase (hTERT) in normal and neoplastic ovary, endometrium and myometrium. Int J Cancer 85(3):330–335PubMedCrossRefGoogle Scholar
  183. 183.
    Holt SE et al (1999) Functional requirement of p23 and Hsp90 in telomerase complexes. Genes Dev 13(7):817–826PubMedCentralPubMedCrossRefGoogle Scholar
  184. 184.
    Cong YS, Wright WE, Shay JW (2002) Human telomerase and its regulation. Microbiol Mol Biol Rev 66(3):407–425PubMedCentralPubMedCrossRefGoogle Scholar

Copyright information

© Springer Basel 2015

Authors and Affiliations

  1. 1.Department of Genetics, Cell and ImmunobiologySemmelweis UniversityBudapestHungary

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