Gene Expression, Epigenetics and Ageing

  • Babukrishna Maniyadath
  • Namrata Shukla
  • Ullas Kolthur-SeetharamEmail author
Part of the Subcellular Biochemistry book series (SCBI, volume 90)


As the popular adage goes, all diseases run into old age and almost all physiological changes are associated with alterations in gene expression, irrespective of whether they are causal or consequential. Therefore, the quest for mechanisms that delay ageing and decrease age-associated diseases has propelled researchers to unravel regulatory factors that lead to changes in chromatin structure and function, which ultimately results in deregulated gene expression. It is therefore essential to bring together literature, which until recently has investigated gene expression and chromatin independently. With advances in biomedical research and the emergence of epigenetic regulators as potential therapeutic targets, enhancing our understanding of mechanisms that ‘derail’ transcription and identification of causal genes/pathways during ageing will have a significant impact. In this context, this chapter aims to not only summarize the key features of age-associated changes in epigenetics and transcription, but also identifies gaps in the field and proposes aspects that need to be investigated in the future.


Ageing Senescence Gene expression Epigenetics Transcriptional Noise Chromatin Histone Variants DNA methylation 5hmC SAHF 


  1. Adams PD (2007) Remodeling of chromatin structure in senescent cells and its potential impact on tumor suppression and ageing. Gene 397:84–93. CrossRefPubMedPubMedCentralGoogle Scholar
  2. Avrahami D et al (2015) Ageing-Dependent Demethylation of Regulatory Elements Correlates with Chromatin State and Improved beta Cell Function. Cell Metab 22:619–632. CrossRefPubMedPubMedCentralGoogle Scholar
  3. Bahar R et al (2006) Increased cell-to-cell variation in gene expression in ageing mouse heart. Nature 441:1011–1014. CrossRefPubMedGoogle Scholar
  4. Baker DJ, Jin F, van Deursen JM (2008) The yin and yang of the Cdkn2a locus in senescence and ageing. Cell Cycle 7:2795–2802. CrossRefPubMedPubMedCentralGoogle Scholar
  5. Balaban RS, Nemoto S, Finkel T (2005) Mitochondria, oxidants, and ageing. Cell 120:483–495. CrossRefPubMedPubMedCentralGoogle Scholar
  6. Balasubramanian D et al (2012) H3K4me3 inversely correlates with DNA methylation at a large class of non-CpG-island-containing start sites. Genome Med 4:47. CrossRefPubMedPubMedCentralGoogle Scholar
  7. Banerjee KK, Ayyub C, Ali SZ, Mandot V, Prasad NG, Kolthur-Seetharam U (2012) dSir2 in the adult fat body, but not in muscles, regulates life span in a diet-dependent manner. Cell Rep 2:1485–1491. CrossRefPubMedGoogle Scholar
  8. Barzilai N, Huffman DM, Muzumdar RH, Bartke A (2012) The critical role of metabolic pathways in ageing. Diabetes 61:1315–1322. CrossRefPubMedPubMedCentralGoogle Scholar
  9. Beerman I, Seita J, Inlay MA, Weissman IL, Rossi DJ (2014) Quiescent hematopoietic stem cells accumulate DNA damage during ageing that is repaired upon entry into cell cycle. Cell Stem Cell 15:37–50. CrossRefPubMedPubMedCentralGoogle Scholar
  10. Berchtold NC et al (2008) Gene expression changes in the course of normal brain ageing are sexually dimorphic. Proc Natl Acad Sci U S A 105:15605–15610. CrossRefPubMedPubMedCentralGoogle Scholar
  11. Bjornsson HT et al (2008) Intra-individual change over time in DNA methylation with familial clustering. JAMA 299:2877–2883. CrossRefPubMedPubMedCentralGoogle Scholar
  12. Bochkis IM, Przybylski D, Chen J, Regev A (2014) Changes in nucleosome occupancy associated with metabolic alterations in aged mammalian liver. Cell Rep 9:996–1006. CrossRefPubMedPubMedCentralGoogle Scholar
  13. Boisvert MM, Erikson GA, Shokhirev MN, Allen NJ (2018) The ageing astrocyte transcriptome from multiple regions of the mouse brain. Cell Rep 22:269–285. CrossRefPubMedPubMedCentralGoogle Scholar
  14. Bonasio R, Shiekhattar R (2014) Regulation of transcription by long noncoding RNAs. Annu Rev Genet 48:433–455. CrossRefPubMedPubMedCentralGoogle Scholar
  15. Bratic I, Trifunovic A (2010) Mitochondrial energy metabolism and ageing. Biochim Biophys Acta 1797:961–967. CrossRefPubMedGoogle Scholar
  16. Burgess RC, Misteli T, Oberdoerffer P (2012) DNA damage, chromatin, and transcription: the trinity of ageing. Curr Opin Cell Biol 24:724–730. CrossRefPubMedPubMedCentralGoogle Scholar
  17. Campisi J (2013) Ageing, cellular senescence, and cancer. Annu Rev Physiol 75:685–705. CrossRefPubMedGoogle Scholar
  18. Carlson ME, Conboy IM (2007) Loss of stem cell regenerative capacity within aged niches. Ageing Cell 6:371–382. CrossRefGoogle Scholar
  19. Chambers SM, Shaw CA, Gatza C, Fisk CJ, Donehower LA, Goodell MA (2007) Ageing hematopoietic stem cells decline in function and exhibit epigenetic dysregulation. PLoS Biol 5:e201. CrossRefPubMedPubMedCentralGoogle Scholar
  20. Chandra T et al (2012) Independence of repressive histone marks and chromatin compaction during senescent heterochromatic layer formation. Mol Cell 47:203–214. CrossRefPubMedPubMedCentralGoogle Scholar
  21. Chandra T et al (2015) Global reorganization of the nuclear landscape in senescent cells. Cell Rep 10:471–483. CrossRefPubMedPubMedCentralGoogle Scholar
  22. Chen JH, Hales CN, Ozanne SE (2007) DNA damage, cellular senescence and organismal ageing: causal or correlative? Nucleic Acids Res 35:7417–7428. CrossRefPubMedPubMedCentralGoogle Scholar
  23. Chen H, Dzitoyeva S, Manev H (2012) Effect of ageing on 5-hydroxymethylcytosine in the mouse hippocampus. Restor Neurol Neurosci 30:237–245. CrossRefPubMedPubMedCentralGoogle Scholar
  24. Chen H, Ruiz PD, McKimpson WM, Novikov L, Kitsis RN, Gamble MJ (2015) MacroH2A1 and ATM Play Opposing Roles in Paracrine Senescence and the Senescence-Associated Secretory Phenotype. Mol Cell 59:719–731. CrossRefPubMedPubMedCentralGoogle Scholar
  25. Cheng J et al (2017) Circular RNA expression profiling of human granulosa cells during maternal ageing reveals novel transcripts associated with assisted reproductive technology outcomes. PLoS One 12:e0177888. CrossRefPubMedPubMedCentralGoogle Scholar
  26. Chouliaras L et al (2012a) Age-related increase in levels of 5-hydroxymethylcytosine in mouse hippocampus is prevented by caloric restriction. Curr Alzheimer Res 9:536–544CrossRefGoogle Scholar
  27. Chouliaras L et al (2012b) Prevention of age-related changes in hippocampal levels of 5-methylcytidine by caloric restriction. Neurobiol Ageing 33:1672–1681. CrossRefGoogle Scholar
  28. Christensen BC et al (2009) Ageing and environmental exposures alter tissue-specific DNA methylation dependent upon CpG island context. PLoS Genet 5:e1000602. CrossRefPubMedPubMedCentralGoogle Scholar
  29. Couvillion MT, Soto IC, Shipkovenska G, Churchman LS (2016) Synchronized mitochondrial and cytosolic translation programs. Nature 533:499–503. CrossRefPubMedPubMedCentralGoogle Scholar
  30. Croft DP, Brent LJ, Franks DW, Cant MA (2015) The evolution of prolonged life after reproduction. Trends Ecol Evol 30:407–416. CrossRefPubMedGoogle Scholar
  31. Dai L et al (2014) Lysine 2-hydroxyisobutyrylation is a widely distributed active histone mark. Nat Chem Biol 10:365–370. CrossRefPubMedGoogle Scholar
  32. Dang W et al (2009) Histone H4 lysine 16 acetylation regulates cellular lifespan. Nature 459:802–807. CrossRefPubMedPubMedCentralGoogle Scholar
  33. de Magalhaes JP, Curado J, Church GM (2009) Meta-analysis of age-related gene expression profiles identifies common signatures of ageing. Bioinformatics 25:875–881. CrossRefPubMedPubMedCentralGoogle Scholar
  34. Dell’Orco RT, Whittle WL (1982) Micrococcal nuclease and DNase I digestion of DNA from ageing human diploid cells. Biochem Biophys Res Commun 107:117–122CrossRefGoogle Scholar
  35. Di Micco R, Cicalese A, Fumagalli M, Dobreva M, Verrecchia A, Pelicci PG, di Fagagna F (2008) DNA damage response activation in mouse embryonic fibroblasts undergoing replicative senescence and following spontaneous immortalization. Cell Cycle 7:3601–3606. CrossRefPubMedGoogle Scholar
  36. Duarte LF et al (2014) Histone H3.3 and its proteolytically processed form drive a cellular senescence programme. Nat Commun 5:5210. CrossRefPubMedPubMedCentralGoogle Scholar
  37. Enge M, Arda HE, Mignardi M, Beausang J, Bottino R, Kim SK, Quake SR (2017) Single-Cell Analysis of Human Pancreas Reveals Transcriptional Signatures of Ageing and Somatic Mutation Patterns. Cell 171:321–330 e314. CrossRefPubMedPubMedCentralGoogle Scholar
  38. Fan J, Krautkramer KA, Feldman JL, Denu JM (2015) Metabolic regulation of histone post-translational modifications. ACS Chem Biol 10:95–108. CrossRefPubMedPubMedCentralGoogle Scholar
  39. Feser J, Tyler J (2011) Chromatin structure as a mediator of ageing. FEBS Lett 585:2041–2048. CrossRefPubMedGoogle Scholar
  40. Feser J, Truong D, Das C, Carson JJ, Kieft J, Harkness T, Tyler JK (2010) Elevated histone expression promotes life span extension. Mol Cell 39:724–735. CrossRefPubMedPubMedCentralGoogle Scholar
  41. Finkel T (2015) The metabolic regulation of ageing. Nat Med 21:1416–1423. CrossRefPubMedGoogle Scholar
  42. Finkielstain GP et al (2009) An extensive genetic program occurring during postnatal growth in multiple tissues. Endocrinology 150:1791–1800. CrossRefPubMedGoogle Scholar
  43. Flatt T, Schmidt PS (2009) Integrating evolutionary and molecular genetics of ageing. Biochim Biophys Acta 1790:951–962. CrossRefPubMedPubMedCentralGoogle Scholar
  44. Fontana L, Partridge L (2015) Promoting health and longevity through diet: from model organisms to humans. Cell 161:106–118. CrossRefPubMedPubMedCentralGoogle Scholar
  45. Fraga MF, Esteller M (2007) Epigenetics and ageing: the targets and the marks. Trends Genet 23:413–418. CrossRefPubMedGoogle Scholar
  46. Frasca D, Blomberg BB, Paganelli R (2017) Ageing, Obesity, and Inflammatory Age-Related Diseases. Front Immunol 8:1745. CrossRefPubMedPubMedCentralGoogle Scholar
  47. Funayama R, Ishikawa F (2007) Cellular senescence and chromatin structure. Chromosoma 116:431–440. CrossRefPubMedGoogle Scholar
  48. Funayama R, Saito M, Tanobe H, Ishikawa F (2006) Loss of linker histone H1 in cellular senescence. J Cell Biol 175:869–880. CrossRefPubMedPubMedCentralGoogle Scholar
  49. Gaubatz J, Ellis M, Chalkley R (1979) Nuclease digestion studies of mouse chromatin as a function of age. J Gerontol 34:672–679CrossRefGoogle Scholar
  50. Girardot F, Lasbleiz C, Monnier V, Tricoire H (2006) Specific age-related signatures in Drosophila body parts transcriptome. BMC Genomics 7:69. CrossRefPubMedPubMedCentralGoogle Scholar
  51. Golden TR, Melov S (2004) Microarray analysis of gene expression with age in individual nematodes. Ageing Cell 3:111–124. CrossRefGoogle Scholar
  52. Gorbunova V, Seluanov A (2016) DNA double strand break repair, ageing and the chromatin connection. Mutat Res 788:2–6. CrossRefPubMedPubMedCentralGoogle Scholar
  53. Gottlieb S, Esposito RE (1989) A new role for a yeast transcriptional silencer gene, SIR2, in regulation of recombination in ribosomal DNA. Cell 56:771–776CrossRefGoogle Scholar
  54. Goudarzi A et al (2016) Dynamic competing histone H4 K5K8 acetylation and butyrylation are hallmarks of highly active gene promoters. Mol Cell 62:169–180. CrossRefPubMedPubMedCentralGoogle Scholar
  55. Gruner H, Cortes-Lopez M, Cooper DA, Bauer M, Miura P (2016) CircRNA accumulation in the ageing mouse brain. Sci Rep 6:38907. CrossRefPubMedPubMedCentralGoogle Scholar
  56. Guarente L (2007) Sirtuins in ageing and disease. Cold Spring Harb Symp Quant Biol 72:483–488. CrossRefPubMedGoogle Scholar
  57. Hall H et al (2017) Transcriptome profiling of ageing Drosophila photoreceptors reveals gene expression trends that correlate with visual senescence. BMC Genomics 18:894. CrossRefPubMedPubMedCentralGoogle Scholar
  58. Hansen TV et al (2004) Dwarfism and impaired gut development in insulin-like growth factor II mRNA-binding protein 1-deficient mice. Mol Cell Biol 24:4448–4464CrossRefGoogle Scholar
  59. Hansen TB, Jensen TI, Clausen BH, Bramsen JB, Finsen B, Damgaard CK, Kjems J (2013) Natural RNA circles function as efficient microRNA sponges. Nature 495:384–388. CrossRefGoogle Scholar
  60. Harries LW (2014) MicroRNAs as Mediators of the Ageing Process. Genes (Basel) 5:656–670. CrossRefGoogle Scholar
  61. He L, Hannon GJ (2004) MicroRNAs: small RNAs with a big role in gene regulation. Nat Rev Genet 5:522–531. CrossRefPubMedGoogle Scholar
  62. Hebert SL, Lanza IR, Nair KS (2010) Mitochondrial DNA alterations and reduced mitochondrial function in ageing. Mech Ageing Dev 131:451–462. CrossRefPubMedPubMedCentralGoogle Scholar
  63. Hu Z et al (2014) Nucleosome loss leads to global transcriptional up-regulation and genomic instability during yeast ageing. Genes Dev 28:396–408. CrossRefPubMedPubMedCentralGoogle Scholar
  64. Ishimi Y, Kojima M, Takeuchi F, Miyamoto T, Yamada M, Hanaoka F (1987) Changes in chromatin structure during ageing of human skin fibroblasts. Exp Cell Res 169:458–467CrossRefGoogle Scholar
  65. Jazwinski SM, Jiang JC, Kim S (2017) Adaptation to metabolic dysfunction during ageing: making the best of a bad situation. Exp Gerontol 107:87–90. CrossRefPubMedGoogle Scholar
  66. Joseph AM et al (2012) The impact of ageing on mitochondrial function and biogenesis pathways in skeletal muscle of sedentary high- and low-functioning elderly individuals. Ageing Cell 11:801–809. CrossRefGoogle Scholar
  67. Kaikkonen MU, Lam MT, Glass CK (2011) Non-coding RNAs as regulators of gene expression and epigenetics. Cardiovasc Res 90:430–440. CrossRefPubMedPubMedCentralGoogle Scholar
  68. Kawakami K, Nakamura A, Ishigami A, Goto S, Takahashi R (2009) Age-related difference of site-specific histone modifications in rat liver. Biogerontology 10:415–421. CrossRefPubMedGoogle Scholar
  69. Kim SN et al (2005) Age-dependent changes of gene expression in the Drosophila head. Neurobiol Ageing 26:1083–1091. CrossRefGoogle Scholar
  70. Kim MJ, Kim MH, Kim SA, Chang JS (2008) Age-related deterioration of hematopoietic stem cells. Int J Stem Cells 1:55–63CrossRefGoogle Scholar
  71. King AD et al (2016) Reversible Regulation of Promoter and Enhancer Histone Landscape by DNA Methylation in Mouse Embryonic Stem Cells. Cell Rep 17:289–302. CrossRefPubMedPubMedCentralGoogle Scholar
  72. Kreiling JA et al (2011) Age-associated increase in heterochromatic marks in murine and primate tissues. Ageing Cell 10:292–304. CrossRefGoogle Scholar
  73. Kutter C et al (2012) Rapid turnover of long noncoding RNAs and the evolution of gene expression. PLoS Genet 8:e1002841. CrossRefPubMedPubMedCentralGoogle Scholar
  74. Kwabi-Addo B, Chung W, Shen L, Ittmann M, Wheeler T, Jelinek J, Issa JP (2007) Age-related DNA methylation changes in normal human prostate tissues. Clin Cancer Res 13:3796–3802. CrossRefPubMedGoogle Scholar
  75. Kwekel JC, Desai VG, Moland CL, Branham WS, Fuscoe JC (2010) Age and sex dependent changes in liver gene expression during the life cycle of the rat. BMC Genomics 11:675. CrossRefPubMedPubMedCentralGoogle Scholar
  76. Larson K et al (2012) Heterochromatin formation promotes longevity and represses ribosomal RNA synthesis. PLoS Genet 8:e1002473. CrossRefPubMedPubMedCentralGoogle Scholar
  77. Latella L et al (2017) DNA damage signalling mediates the functional antagonism between replicative senescence and terminal muscle differentiation. Genes Dev 31:648–659. CrossRefPubMedPubMedCentralGoogle Scholar
  78. Latorre-Pellicer A et al (2016) Mitochondrial and nuclear DNA matching shapes metabolism and healthy ageing. Nature 535:561–565. CrossRefPubMedGoogle Scholar
  79. Lazarus A, Banerjee KK, Kolthur-Seetharam U (2013) Small changes, big effects: chromatin goes ageing. Subcell Biochem 61:151–176. CrossRefPubMedGoogle Scholar
  80. Li Y et al (2016) Molecular coupling of histone crotonylation and active transcription by AF9 YEATS Domain. Mol Cell 62:181–193. CrossRefPubMedPubMedCentralGoogle Scholar
  81. Lindner H, Sarg B, Grunicke H, Helliger W (1999) Age-dependent deamidation of H1(0) histones in chromatin of mammalian tissues. J Cancer Res Clin Oncol 125:182–186CrossRefGoogle Scholar
  82. Liu L et al (2013) Chromatin modifications as determinants of muscle stem cell quiescence and chronological ageing. Cell Rep 4:189–204. CrossRefPubMedPubMedCentralGoogle Scholar
  83. Lopez-Otin C, Blasco MA, Partridge L, Serrano M, Kroemer G (2013) The hallmarks of ageing. Cell 153:1194–1217. CrossRefPubMedPubMedCentralGoogle Scholar
  84. Lu C, Thompson CB (2012) Metabolic regulation of epigenetics. Cell Metab 16:9–17. CrossRefPubMedPubMedCentralGoogle Scholar
  85. Lu T, Pan Y, Kao SY, Li C, Kohane I, Chan J, Yankner BA (2004) Gene regulation and DNA damage in the ageing human brain. Nature 429:883–891. CrossRefPubMedGoogle Scholar
  86. Lui JC, Chen W, Barnes KM, Baron J (2010) Changes in gene expression associated with ageing commonly originate during juvenile growth. Mech Ageing Dev 131:641–649. CrossRefPubMedPubMedCentralGoogle Scholar
  87. Maedler K, Schumann DM, Schulthess F, Oberholzer J, Bosco D, Berney T, Donath MY (2006) Ageing correlates with decreased beta-cell proliferative capacity and enhanced sensitivity to apoptosis: a potential role for Fas and pancreatic duodenal homeobox-1. Diabetes 55:2455–2462. CrossRefPubMedGoogle Scholar
  88. Maegawa S et al (2010) Widespread and tissue specific age-related DNA methylation changes in mice. Genome Res 20:332–340. CrossRefPubMedPubMedCentralGoogle Scholar
  89. Martinez-Jimenez CP et al (2017) Ageing increases cell-to-cell transcriptional variability upon immune stimulation. Science 355:1433–1436. CrossRefPubMedPubMedCentralGoogle Scholar
  90. Maze I et al (2015) Critical Role of Histone Turnover in Neuronal Transcription and Plasticity. Neuron 87:77–94. CrossRefPubMedPubMedCentralGoogle Scholar
  91. Medvedev ZA, Medvedeva MN (1990) Age-related changes of the H1 and H1(0) histone variants in murine tissues. Exp Gerontol 25:189–200CrossRefGoogle Scholar
  92. Memczak S et al (2013) Circular RNAs are a large class of animal RNAs with regulatory potency. Nature 495:333–338. CrossRefGoogle Scholar
  93. Mieczkowski J et al (2016) MNase titration reveals differences between nucleosome occupancy and chromatin accessibility. Nat Commun 7:11485. CrossRefPubMedPubMedCentralGoogle Scholar
  94. Morimoto S, Komatsu S, Takahashi R, Matsuo M, Goto S (1993) Age-related change in the amount of ubiquitinated histones in the mouse brain. Arch Gerontol Geriatr 16:217–224CrossRefGoogle Scholar
  95. Morselli M et al (2015) In vivo targeting of de novo DNA methylation by histone modifications in yeast and mouse. Elife 4:e06205. CrossRefPubMedPubMedCentralGoogle Scholar
  96. Munoz-Culla M et al (2017) Progressive changes in non-coding RNA profile in leucocytes with age. Ageing (Albany NY) 9:1202–1218. CrossRefGoogle Scholar
  97. Murphy CT et al (2003) Genes that act downstream of DAF-16 to influence the lifespan of Caenorhabditis elegans. Nature 424:277–283. CrossRefPubMedPubMedCentralGoogle Scholar
  98. Narita M (2007) Cellular senescence and chromatin organisation. Br J Cancer 96:686–691. CrossRefPubMedPubMedCentralGoogle Scholar
  99. Narita M et al (2003) Rb-mediated heterochromatin formation and silencing of E2F target genes during cellular senescence. Cell 113:703–716CrossRefGoogle Scholar
  100. Narita M et al (2006) A novel role for high-mobility group a proteins in cellular senescence and heterochromatin formation. Cell 126:503–514. CrossRefPubMedGoogle Scholar
  101. Newman JC et al (2017) Ketogenic diet reduces midlife mortality and improves memory in ageing mice. Cell Metab 26:547–557 e548. CrossRefPubMedPubMedCentralGoogle Scholar
  102. Niccoli T, Partridge L (2012) Ageing as a risk factor for disease. Curr Biol 22:R741–R752. CrossRefPubMedGoogle Scholar
  103. Nishino J, Kim I, Chada K, Morrison SJ (2008) Hmga2 promotes neural stem cell self-renewal in young but not old mice by reducing p16Ink4a and p19Arf Expression. Cell 135:227–239. CrossRefPubMedPubMedCentralGoogle Scholar
  104. Oberdoerffer P et al (2008) SIRT1 redistribution on chromatin promotes genomic stability but alters gene expression during ageing. Cell 135:907–918. CrossRefPubMedPubMedCentralGoogle Scholar
  105. O'Sullivan RJ, Karlseder J (2012) The great unravelling: chromatin as a modulator of the ageing process. Trends Biochem Sci 37:466–476. CrossRefPubMedPubMedCentralGoogle Scholar
  106. O'Sullivan RJ, Kubicek S, Schreiber SL, Karlseder J (2010) Reduced histone biosynthesis and chromatin changes arising from a damage signal at telomeres. Nat Struct Mol Biol 17:1218–1225. CrossRefPubMedPubMedCentralGoogle Scholar
  107. Owsley C (2016) Vision and ageing. Annu Rev Vis Sci 2:255–271. CrossRefPubMedGoogle Scholar
  108. Pal S, Tyler JK (2016) Epigenetics and ageing. Sci Adv 2:e1600584. CrossRefPubMedPubMedCentralGoogle Scholar
  109. Pan L, Penney J, Tsai LH (2014) Chromatin regulation of DNA damage repair and genome integrity in the central nervous system. J Mol Biol 426:3376–3388. CrossRefPubMedPubMedCentralGoogle Scholar
  110. Panda AC et al (2017a) Identification of senescence-associated circular RNAs (SAC-RNAs) reveals senescence suppressor CircPVT1. Nucleic Acids Res 45:4021–4035. CrossRefPubMedGoogle Scholar
  111. Panda AC, Grammatikakis I, Munk R, Gorospe M, Abdelmohsen K (2017b) Emerging roles and context of circular RNAs. Wiley Interdiscip Rev RNA 8:e1386. CrossRefGoogle Scholar
  112. Parsons PA (2007) The ecological stress theory of ageing and hormesis: an energetic evolutionary model. Biogerontology 8:233–242. CrossRefPubMedGoogle Scholar
  113. Patil VS, Zhou R, Rana TM (2014) Gene regulation by non-coding RNAs. Crit Rev Biochem Mol Biol 49:16–32. CrossRefPubMedGoogle Scholar
  114. Peleg S, Feller C, Ladurner AG, Imhof A (2016) The Metabolic Impact on Histone Acetylation and Transcription in Ageing. Trends Biochem Sci 41:700–711. CrossRefPubMedGoogle Scholar
  115. Pfeifer GP, Kadam S, Jin SG (2013) 5-hydroxymethylcytosine and its potential roles in development and cancer. Epigenetics Chromatin 6:10. CrossRefPubMedPubMedCentralGoogle Scholar
  116. Piazzesi A, Papic D, Bertan F, Salomoni P, Nicotera P, Bano D (2016) Replication-Independent Histone Variant H3.3 Controls Animal Lifespan through the Regulation of Pro-longevity Transcriptional Programs. Cell Rep 17:987–996. CrossRefPubMedPubMedCentralGoogle Scholar
  117. Pina B, Suau P (1987) Changes in histones H2A and H3 variant composition in differentiating and mature rat brain cortical neurons. Dev Biol 123:51–58CrossRefGoogle Scholar
  118. Pollina EA, Brunet A (2011) Epigenetic regulation of ageing stem cells. Oncogene 30:3105–3126. CrossRefPubMedGoogle Scholar
  119. Raddatz G et al (2013) Ageing is associated with highly defined epigenetic changes in the human epidermis. Epigenetics Chromatin 6:36. CrossRefPubMedPubMedCentralGoogle Scholar
  120. Rakyan VK et al (2010) Human ageing-associated DNA hypermethylation occurs preferentially at bivalent chromatin domains. Genome Res 20:434–439. CrossRefPubMedPubMedCentralGoogle Scholar
  121. Rangaraju S et al (2015) Suppression of transcriptional drift extends C elegans lifespan by postponing the onset of mortality. Elife 4:e08833. CrossRefPubMedPubMedCentralGoogle Scholar
  122. Rastogi S, Joshi B, Dasgupta P, Morris M, Wright K, Chellappan S (2006) Prohibitin facilitates cellular senescence by recruiting specific corepressors to inhibit E2F target genes. Mol Cell Biol 26:4161–4171. CrossRefPubMedPubMedCentralGoogle Scholar
  123. Rath PC, Kanungo MS (1989) Methylation of repetitive DNA sequences in the brain during ageing of the rat. FEBS Lett 244:193–198CrossRefGoogle Scholar
  124. Raz N, Rodrigue KM, Head D, Kennedy KM, Acker JD (2004) Differential ageing of the medial temporal lobe: a study of a five-year change. Neurology 62:433–438CrossRefGoogle Scholar
  125. Rhie BH, Song YH, Ryu HY, Ahn SH (2013) Cellular ageing is associated with increased ubiquitylation of histone H2B in yeast telomeric heterochromatin. Biochem Biophys Res Commun 439:570–575. CrossRefPubMedGoogle Scholar
  126. Richter-Dennerlein R et al (2016) Mitochondrial protein synthesis adapts to influx of nuclear-encoded protein. Cell 167:471–483 e410. CrossRefPubMedPubMedCentralGoogle Scholar
  127. Rinn JL, Chang HY (2012) Genome regulation by long noncoding RNAs. Annu Rev Biochem 81:145–166. CrossRefPubMedGoogle Scholar
  128. Rodrigues HF, Souza TA, Ghiraldini FG, Mello ML, Moraes AS (2014) Increased age is associated with epigenetic and structural changes in chromatin from neuronal nuclei. J Cell Biochem 115:659–665. CrossRefPubMedGoogle Scholar
  129. Rodwell GE et al (2004) A transcriptional profile of ageing in the human kidney. PLoS Biol 2:e427. CrossRefPubMedPubMedCentralGoogle Scholar
  130. Rogakou EP, Sekeri-Pataryas KE (1999) Histone variants of H2A and H3 families are regulated during in vitro ageing in the same manner as during differentiation. Exp Gerontol 34:741–754CrossRefGoogle Scholar
  131. Rose NR, Klose RJ (2014) Understanding the relationship between DNA methylation and histone lysine methylation. Biochim Biophys Acta 1839:1362–1372. CrossRefPubMedPubMedCentralGoogle Scholar
  132. Sabari BR et al (2015) Intracellular crotonyl-CoA stimulates transcription through p300-catalyzed histone crotonylation. Mol Cell 58:203–215. CrossRefPubMedPubMedCentralGoogle Scholar
  133. Sabari BR, Zhang D, Allis CD, Zhao Y (2017) Metabolic regulation of gene expression through histone acylations. Nat Rev Mol Cell Biol 18:90–101. CrossRefPubMedGoogle Scholar
  134. Sadaie M et al (2013) Redistribution of the Lamin B1 genomic binding profile affects rearrangement of heterochromatic domains and SAHF formation during senescence. Genes Dev 27:1800–1808. CrossRefPubMedPubMedCentralGoogle Scholar
  135. Sandovici I et al (2011) Maternal diet and ageing alter the epigenetic control of a promoter-enhancer interaction at the Hnf4a gene in rat pancreatic islets. Proc Natl Acad Sci U S A 108:5449–5454. CrossRefPubMedPubMedCentralGoogle Scholar
  136. Sarg B, Koutzamani E, Helliger W, Rundquist I, Lindner HH (2002) Postsynthetic trimethylation of histone H4 at lysine 20 in mammalian tissues is associated with ageing. J Biol Chem 277:39195–39201. CrossRefPubMedGoogle Scholar
  137. Scaffidi P, Misteli T (2006) Lamin A-dependent nuclear defects in human ageing. Science 312:1059–1063. CrossRefPubMedPubMedCentralGoogle Scholar
  138. Schellenberg A, Stiehl T, Horn P, Joussen S, Pallua N, Ho AD, Wagner W (2012) Population dynamics of mesenchymal stromal cells during culture expansion. Cytotherapy 14:401–411. CrossRefPubMedGoogle Scholar
  139. Schotta G et al (2008) A chromatin-wide transition to H4K20 monomethylation impairs genome integrity and programmed DNA rearrangements in the mouse. Genes Dev 22:2048–2061. CrossRefPubMedPubMedCentralGoogle Scholar
  140. Sinclair DA, Guarente L (1997) Extrachromosomal rDNA circles–a cause of ageing in yeast. Cell 91:1033–1042CrossRefGoogle Scholar
  141. Smith JS, Boeke JD (1997) An unusual form of transcriptional silencing in yeast ribosomal. DNA Genes Dev 11:241–254CrossRefGoogle Scholar
  142. Smith-Vikos T, Slack FJ (2012) MicroRNAs and their roles in ageing. J Cell Sci 125:7–17. CrossRefPubMedPubMedCentralGoogle Scholar
  143. Southworth LK, Owen AB, Kim SK (2009) Ageing mice show a decreasing correlation of gene expression within genetic modules. PLoS Genet 5:e1000776. CrossRefPubMedPubMedCentralGoogle Scholar
  144. Sproul D, Gilbert N, Bickmore WA (2005) The role of chromatin structure in regulating the expression of clustered genes. Nat Rev Genet 6:775–781. CrossRefPubMedGoogle Scholar
  145. Spurlock CF, 3rd, Crooke PS, 3rd, Aune TM (2016) Biogenesis and transcriptional regulation of long noncoding RNAs in the human immune system J Immunol 197:4509–4517 doi:
  146. Stefanelli G et al (2018) Learning and age-related changes in genome-wide H2A.Z binding in the mouse hippocampus. Cell Rep 22:1124–1131. CrossRefPubMedPubMedCentralGoogle Scholar
  147. Sun D et al (2014) Epigenomic profiling of young and aged HSCs reveals concerted changes during ageing that reinforce self-renewal. Cell Stem Cell 14:673–688. CrossRefPubMedPubMedCentralGoogle Scholar
  148. Szulwach KE et al (2011) 5-hmC-mediated epigenetic dynamics during postnatal neurodevelopment and ageing. Nat Neurosci 14:1607–1616. CrossRefPubMedPubMedCentralGoogle Scholar
  149. Takasugi M (2011) Progressive age-dependent DNA methylation changes start before adulthood in mouse tissues. Mech Ageing Dev 132:65–71. CrossRefPubMedGoogle Scholar
  150. Tan L, Shi YG (2012) Tet family proteins and 5-hydroxymethylcytosine in development and disease. Development 139:1895–1902. CrossRefPubMedPubMedCentralGoogle Scholar
  151. Thakur MK, Asaithambi A, Mukherjee S (1999) Sex-specific alterations in chromatin conformation of the brain of ageing mouse. Mol Biol Rep 26:239–247CrossRefGoogle Scholar
  152. Thomas RP, Guigneaux M, Wood T, Evers BM (2002) Age-associated changes in gene expression patterns in the liver. J Gastrointest Surg 6:445–453 discussion 454CrossRefGoogle Scholar
  153. Tsai K-L, Chen L-H, Chen Y-C, Kao C-L, Chen L-K, Chiou S-H (2011) The role of microRNAs in modulating sirtuin 1 expression. Journal of Clinical Gerontology and Geriatrics 2:71–75. CrossRefGoogle Scholar
  154. Ungvari Z, Labinskyy N, Gupte S, Chander PN, Edwards JG, Csiszar A (2008) Dysregulation of mitochondrial biogenesis in vascular endothelial and smooth muscle cells of aged rats. Am J Physiol Heart Circ Physiol 294:H2121–H2128. CrossRefPubMedGoogle Scholar
  155. Valinezhad Orang A, Safaralizadeh R, Kazemzadeh-Bavili M (2014) Mechanisms of miRNA-Mediated Gene Regulation from Common Downregulation to mRNA-Specific Upregulation. Int J Genomics 2014:970607. CrossRefPubMedPubMedCentralGoogle Scholar
  156. Van Meter M, Kashyap M, Rezazadeh S, Geneva AJ, Morello TD, Seluanov A, Gorbunova V (2014) SIRT6 represses LINE1 retrotransposons by ribosylating KAP1 but this repression fails with stress and age. Nat Commun 5:5011. CrossRefPubMedPubMedCentralGoogle Scholar
  157. Venkatesh S, Workman JL (2015) Histone exchange, chromatin structure and the regulation of transcription. Nat Rev Mol Cell Biol 16:178–189. CrossRefPubMedGoogle Scholar
  158. Vijay V, Han T, Moland CL, Kwekel JC, Fuscoe JC, Desai VG (2015) Sexual dimorphism in the expression of mitochondria-related genes in rat heart at different ages. PLoS One 10:e0117047. CrossRefPubMedPubMedCentralGoogle Scholar
  159. Wang Q, Huang J, Zhang X, Wu B, Liu X, Shen Z (2011) The spatial association of gene expression evolves from synchrony to asynchrony and stochasticity with age. PLoS One 6:e24076. CrossRefPubMedPubMedCentralGoogle Scholar
  160. Warner JR (1999) The economics of ribosome biosynthesis in yeast. Trends Biochem Sci 24:437–440CrossRefGoogle Scholar
  161. Warren LA, Rossi DJ, Schiebinger GR, Weissman IL, Kim SK, Quake SR (2007) Transcriptional instability is not a universal attribute of ageing. Ageing Cell 6:775–782. CrossRefGoogle Scholar
  162. Welle S, Brooks AI, Delehanty JM, Needler N, Thornton CA (2003) Gene expression profile of ageing in human muscle. Physiol Genomics 14:149–159. CrossRefPubMedGoogle Scholar
  163. Westholm JO et al (2014) Genome-wide analysis of drosophila circular RNAs reveals their structural and sequence properties and age-dependent neural accumulation. Cell Rep 9:1966–1980. CrossRefPubMedPubMedCentralGoogle Scholar
  164. White RR, Milholland B, MacRae SL, Lin M, Zheng D, Vijg J (2015) Comprehensive transcriptional landscape of ageing mouse liver. BMC Genomics 16:899. CrossRefPubMedPubMedCentralGoogle Scholar
  165. Wierman MB, Smith JS (2014) Yeast sirtuins and the regulation of ageing. FEMS Yeast Res 14:73–88. CrossRefPubMedGoogle Scholar
  166. Wilson VL, Smith RA, Ma S, Cutler RG (1987) Genomic 5-methyldeoxycytidine decreases with age. J Biol Chem 262:9948–9951PubMedGoogle Scholar
  167. Wood JG et al (2010) Chromatin remodeling in the ageing genome of Drosophila. Ageing Cell 9:971–978. CrossRefGoogle Scholar
  168. Wood SH, Craig T, Li Y, Merry B, de Magalhaes JP (2013) Whole transcriptome sequencing of the ageing rat brain reveals dynamic RNA changes in the dark matter of the genome. Age (Dordr) 35:763–776. CrossRefGoogle Scholar
  169. Wyss-Coray T (2016) Ageing, neurodegeneration and brain rejuvenation. Nature 539:180–186. CrossRefPubMedPubMedCentralGoogle Scholar
  170. Zhan M, Yamaza H, Sun Y, Sinclair J, Li H, Zou S (2007) Temporal and spatial transcriptional profiles of ageing in Drosophila melanogaster. Genome Res 17:1236–1243. CrossRefPubMedPubMedCentralGoogle Scholar
  171. Zhang Y, Hood WR (2016) Current versus future reproduction and longevity: a re-evaluation of predictions and mechanisms. J Exp Biol 219:3177–3189. CrossRefPubMedPubMedCentralGoogle Scholar
  172. Zhang R et al (2005) Formation of MacroH2A-containing senescence-associated heterochromatin foci and senescence driven by ASF1a and HIRA. Dev Cell 8:19–30. CrossRefPubMedGoogle Scholar
  173. Zhang R, Chen W, Adams PD (2007) Molecular dissection of formation of senescence-associated heterochromatin foci. Mol Cell Biol 27:2343–2358. CrossRefPubMedPubMedCentralGoogle Scholar
  174. Zongza V, Mathias AP (1979) The variation with age of the structure of chromatin in three cell types from rat liver. Biochem J 179:291–298CrossRefGoogle Scholar

Copyright information

© Springer Nature Singapore Pte Ltd. 2018

Authors and Affiliations

  • Babukrishna Maniyadath
    • 1
  • Namrata Shukla
    • 1
  • Ullas Kolthur-Seetharam
    • 1
    Email author
  1. 1.Department of Biological SciencesTata Institute of Fundamental ResearchMumbaiIndia

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