The peculiar genetics of the ribosomal DNA blurs the boundaries of transgenerational epigenetic inheritance

  • Farah Bughio
  • Keith A. Maggert


Our goal is to draw a line—hypothetical in its totality but experimentally supported at each individual step—connecting the ribosomal DNA and the phenomenon of transgenerational epigenetic inheritance of induced phenotypes. The reasonableness of this hypothesis is offset by its implication, that many (or most) (or all) of the cases of induced-and-inherited phenotypes that are seen to persist for generations are instead unmapped induced polymorphisms in the ribosomal DNA, and thus are the consequence of the peculiar and enduringly fascinating genetics of the highly transcribed repeat DNA structure at that locus.


rDNA Ribosomal DNA Epigenetics 



Bloom syndrome protein


CCCTC-binding factor


Genome-wide association study


Inverted repeat


Long terminal repeat


Quantitative trait locus


Reverse transcription-quantitative polymerase chain reaction


Suppressor of variation



We gratefully acknowledge Drs. Pamela Geyer, C.-Ting Wu, and Harmit Malik for the encouragement.

Author contribution statement

FB and KAM wrote, read, and approved the manuscript.

Funding information

The work was funded by an NIH Director’s Transformative Research Award (1R01GM123640), and support was provided by the UA. Cancer Center Core Grant (P30CA023074).


  1. Ahmad Y, Boisvert FM, Gregor P, Cobley A, Lamond AI (2009) NOPdb: nucleolar proteome database--2008 update. Nucleic Acids Res 37:D181–D184CrossRefGoogle Scholar
  2. Aldrich JC, Maggert KA (2014) Simple quantitative PCR approach to reveal naturally occurring and mutation-induced repetitive sequence variation on the Drosophila Y chromosome. PLoS One 9:e109906PubMedCentralCrossRefPubMedGoogle Scholar
  3. Aldrich JC, Maggert KA (2015) Transgenerational inheritance of diet-induced genome rearrangements in Drosophila. PLoS Genet 11:e1005148PubMedCentralCrossRefPubMedGoogle Scholar
  4. Andersen JS, Lam YW, Leung AK, Ong SE, Lyon CE et al (2005) Nucleolar proteome dynamics. Nature 433:77–83CrossRefGoogle Scholar
  5. Anway MD, Cupp AS, Uzumcu M, Skinner MK (2005) Epigenetic transgenerational actions of endocrine disruptors and male fertility. Science 308:1466–1469CrossRefGoogle Scholar
  6. Ashburner M, Golic KG, Hawley RS (2005) Drosophila: a laboratory handbook. Cold Spring Harbor Laboratory Press, Cold Spring HarborGoogle Scholar
  7. Averbeck KT, Eickbush TH (2005) Monitoring the mode and tempo of concerted evolution in the Drosophila melanogaster rDNA locus. Genetics 171:1837–1846PubMedCentralCrossRefPubMedGoogle Scholar
  8. Beiko NN, Terekhov SM, Shubaeva NO, Simirnova TD, Ivanova SM et al (2005) Early and late responses to oxidative stress in human dermal fibroblasts of healthy donors and rheumatoid arthritis patients. Relationship between the cell death rate and the genomic dosage of active ribosomal genes. Mol Biol (Mosk) 39:264–275Google Scholar
  9. Berger SL, Kouzarides T, Shiekhattar R, Shilatifard A (2009) An operational definition of epigenetics. Genes Dev 23:781–783PubMedCentralCrossRefPubMedGoogle Scholar
  10. Bianciardi A, Boschi M, Swanson EE, Belloni M, Robbins LG (2012) Ribosomal DNA organization before and after magnification in Drosophila melanogaster. Genetics 191:703–723PubMedCentralCrossRefPubMedGoogle Scholar
  11. Braunschweig M, Jagannathan V, Gutzwiller A, Bee G (2012) Investigations on transgenerational epigenetic response down the male line in F2 pigs. PLoS One 7:e30583PubMedCentralCrossRefPubMedGoogle Scholar
  12. Carone BR, Fauquier L, Habib N, Shea JM, Hart CE, Li R, Bock C, Li C, Gu H, Zamore PD, Meissner A, Weng Z, Hofmann HA, Friedman N, Rando OJ (2010) Paternally induced transgenerational environmental reprogramming of metabolic gene expression in mammals. Cell 143:1084–1096PubMedCentralCrossRefPubMedGoogle Scholar
  13. Chen ZJ, Comai L, Pikaard CS (1998) Gene dosage and stochastic effects determine the severity and direction of uniparental ribosomal RNA gene silencing (nucleolar dominance) in Arabidopsis allopolyploids. Proc Natl Acad Sci U S A 95:14891–14896PubMedCentralCrossRefPubMedGoogle Scholar
  14. Chen J, Lobb IT, Morin P, Novo SM, Simpson J, Kennerknecht K, von Kriegsheim A, Batchelor EE, Oakley F, Stark LA (2018) Identification of a novel TIF-IA-NF-kappaB nucleolar stress response pathway. Nucleic Acids Res 46:6188–6205PubMedCentralCrossRefPubMedGoogle Scholar
  15. Cheung SW, Sun L, Featherstone T (1990) Molecular cytogenetic evidence to characterize breakpoint regions in Robertsonian translocations. Cytogenet Cell Genet 54:97–102CrossRefGoogle Scholar
  16. Cohen S, Yacobi K, Segal D (2003) Extrachromosomal circular DNA of tandemly repeated genomic sequences in Drosophila. Genome Res 13:1133–1145PubMedCentralCrossRefPubMedGoogle Scholar
  17. Cohen S, Agmon N, Yacobi K, Mislovati M, Segal D (2005) Evidence for rolling circle replication of tandem genes in Drosophila. Nucleic Acids Res 33:4519–4526PubMedCentralCrossRefPubMedGoogle Scholar
  18. Cohen S, Houben A, Segal D (2008) Extrachromosomal circular DNA derived from tandemly repeated genomic sequences in plants. Plant J 53:1027–1034CrossRefGoogle Scholar
  19. Cullis CA, Cleary W (1986) Rapidly varying DNA sequences in flax. Can J Genet Cytol 28:252–259CrossRefGoogle Scholar
  20. Danson AF, Marzi SJ, Lowe R, Holland ML, Rakyan VK (2018) Early life diet conditions the molecular response to post-weaning protein restriction in the mouse. BMC Biol 16:51PubMedCentralCrossRefPubMedGoogle Scholar
  21. Daroit NB, Salgueiro AP, Maito F, Visioli F, Rados PV (2018) The use of cytopathology to identify disturbances in oral squamous cell carcinoma at early stage: a case report. Diagn CytopatholGoogle Scholar
  22. Eickbush DG, Eickbush TH (2003) Transcription of endogenous and exogenous R2 elements in the rRNA gene locus of Drosophila melanogaster. Mol Cell Biol 23:3825–3836PubMedCentralCrossRefPubMedGoogle Scholar
  23. Eickbush TH, Burke WD, Eickbush DG, Lathe WC 3rd (1997) Evolution of R1 and R2 in the rDNA units of the genus Drosophila. Genetica 100:49–61CrossRefGoogle Scholar
  24. Eickbush DG, Ye J, Zhang X, Burke WD, Eickbush TH (2008) Epigenetic regulation of retrotransposons within the nucleolus of Drosophila. Mol Cell Biol 28:6452–6461PubMedCentralCrossRefPubMedGoogle Scholar
  25. Endow SA (1980) On ribosomal gene compensation in Drosophila. Cell 22:149–155CrossRefGoogle Scholar
  26. Endow SA (1982) Molecular characterization of ribosomal genes on the Ybb-chromosome of Drosophila melanogaster. Genetics 102:91–99PubMedCentralPubMedGoogle Scholar
  27. Endow SA (1983) Nucleolar dominance in polytene cells of Drosophila. Proc Natl Acad Sci U S A 80:4427–4431PubMedCentralCrossRefPubMedGoogle Scholar
  28. Endow SA, Komma DJ, Atwood KC (1984) Ring chromosomes and rDNA magnification in Drosophila. Genetics 108:969–983PubMedCentralPubMedGoogle Scholar
  29. Foss EJ, Lao U, Dalrymple E, Adrianse RL, Loe T, Bedalov A (2017) SIR2 suppresses replication gaps and genome instability by balancing replication between repetitive and unique sequences. Proc Natl Acad Sci U S A 114:552–557PubMedCentralCrossRefPubMedGoogle Scholar
  30. Gibbons JG, Branco AT, Godinho SA, Yu S, Lemos B (2015) Concerted copy number variation balances ribosomal DNA dosage in human and mouse genomes. Proc Natl Acad Sci U S A 112:2485–2490PubMedCentralCrossRefPubMedGoogle Scholar
  31. Greer EL, Maures TJ, Ucar D, Hauswirth AG, Mancini E, Lim JP, Benayoun BA, Shi Y, Brunet A (2011) Transgenerational epigenetic inheritance of longevity in Caenorhabditis elegans. Nature 479:365–371PubMedCentralCrossRefPubMedGoogle Scholar
  32. Greil F, Ahmad K (2012) Nucleolar dominance of the Y chromosome in Drosophila melanogaster. Genetics 191:1119–1128PubMedCentralCrossRefPubMedGoogle Scholar
  33. Grierson PM, Lillard K, Behbehani GK, Combs KA, Bhattacharyya S, Acharya S, Groden J (2012) BLM helicase facilitates RNA polymerase I-mediated ribosomal RNA transcription. Hum Mol Genet 21:1172–1183CrossRefGoogle Scholar
  34. Grimaldi G, Di Nocera PP (1988) Multiple repeated units in Drosophila melanogaster ribosomal DNA spacer stimulate rRNA precursor transcription. Proc Natl Acad Sci U S A 85:5502–5506PubMedCentralCrossRefPubMedGoogle Scholar
  35. Grummt I, Langst G (2013) Epigenetic control of RNA polymerase I transcription in mammalian cells. Biochim Biophys Acta 1829:393–404CrossRefPubMedPubMedCentralGoogle Scholar
  36. Guerrero PA, Maggert KA (2011) The CCCTC-binding factor (CTCF) of Drosophila contributes to the regulation of the ribosomal DNA and nucleolar stability. PLoS One 6:e16401PubMedCentralCrossRefPubMedGoogle Scholar
  37. Guetg C, Lienemann P, Sirri V, Grummt I, Hernandez-Verdun D, Hottiger MO, Fussenegger M, Santoro R (2010) The NoRC complex mediates the heterochromatin formation and stability of silent rRNA genes and centromeric repeats. EMBO J 29:2135–2146PubMedCentralCrossRefPubMedGoogle Scholar
  38. Hawley RS, Marcus CH (1989) Recombinational controls of rDNA redundancy in Drosophila. Annu Rev Genet 23:87–120CrossRefPubMedPubMedCentralGoogle Scholar
  39. Hawley RS, Tartof KD (1985) A two-stage model for the control of rDNA magnification. Genetics 109:691–700PubMedCentralPubMedGoogle Scholar
  40. Hayward DC, Glover DM (1988) Analysis of the Drosophila rDNA promoter by transient expression. Nucleic Acids Res 16:4253–4268PubMedCentralCrossRefPubMedGoogle Scholar
  41. Heard E, Martienssen RA (2014) Transgenerational epigenetic inheritance: myths and mechanisms. Cell 157:95–109PubMedCentralCrossRefPubMedGoogle Scholar
  42. Holland ML, Lowe R, Caton PW, Gemma C, Carbajosa G, Danson AF, Carpenter AAM, Loche E, Ozanne SE, Rakyan VK (2016) Early-life nutrition modulates the epigenetic state of specific rDNA genetic variants in mice. In: Science, vol 353, pp 495–498Google Scholar
  43. Hurley JE, Pathak S (1977) Elimination of nucleolus organizers in a case of 13/14 Robertsonian translocation. Hum Genet 35:169–173CrossRefGoogle Scholar
  44. Ianni A, Hoelper S, Krueger M, Braun T, Bober E (2017) Sirt7 stabilizes rDNA heterochromatin through recruitment of DNMT1 and Sirt1. Biochem Biophys Res Commun 492:434–440CrossRefGoogle Scholar
  45. Jesse S, Bayer H, Alupei MC, Zugel M, Mulaw M et al (2017) Ribosomal transcription is regulated by PGC-1alpha and disturbed in Huntington’s disease. Sci Rep 7:8513PubMedCentralCrossRefPubMedGoogle Scholar
  46. Killen MW, Stults DM, Wilson WA, Pierce AJ (2012) Escherichia coli RecG functionally suppresses human Bloom syndrome phenotypes. BMC Mol Biol 13:33PubMedCentralCrossRefPubMedGoogle Scholar
  47. Kim JH, Dilthey AT, Nagaraja R, Lee HS, Koren S, Dudekula D, Wood III WH, Piao Y, Ogurtsov AY, Utani K, Noskov VN, Shabalina SA, Schlessinger D, Phillippy AM, Larionov V (2018) Variation in human chromosome 21 ribosomal RNA genes characterized by TAR cloning and long-read sequencing. Nucleic Acids Res 46:6712–6725PubMedCentralCrossRefPubMedGoogle Scholar
  48. Klosin A, Casas E, Hidalgo-Carcedo C, Vavouri T, Lehner B (2017) Transgenerational transmission of environmental information in C. elegans. Science 356:320–323CrossRefGoogle Scholar
  49. Kobayashi T (2008) A new role of the rDNA and nucleolus in the nucleus--rDNA instability maintains genome integrity. Bioessays 30:267–272CrossRefGoogle Scholar
  50. Kobayashi T (2014) Ribosomal RNA gene repeats, their stability and cellular senescence. Proceedings of the Japan Academy, Series B 90:119–129CrossRefGoogle Scholar
  51. Kobayashi T, Heck DJ, Nomura M, Horiuchi T (1998) Expansion and contraction of ribosomal DNA repeats in Saccharomyces cerevisiae: requirement of replication fork blocking (Fob1) protein and the role of RNA polymerase I. Genes Dev 12:3821–3830PubMedCentralCrossRefPubMedGoogle Scholar
  52. Kobayashi T, Nomura M, Horiuchi T (2001) Identification of DNA cis elements essential for expansion of ribosomal DNA repeats in Saccharomyces cerevisiae. Mol Cell Biol 21:136–147PubMedCentralCrossRefPubMedGoogle Scholar
  53. Kojima KK, Fujiwara H (2003) Evolution of target specificity in R1 clade non-LTR retrotransposons. Mol Biol Evol 20:351–361CrossRefGoogle Scholar
  54. Komma DJ, Endow SA (1987) Incomplete Y chromosomes promote magnification in male and female Drosophila. Proc Natl Acad Sci U S A 84:2382–2386PubMedCentralCrossRefPubMedGoogle Scholar
  55. Kuhn A, Deppert U, Grummt I (1990) A 140-base-pair repetitive sequence element in the mouse rRNA gene spacer enhances transcription by RNA polymerase I in a cell-free system. Proc Natl Acad Sci U S A 87:7527–7531PubMedCentralCrossRefPubMedGoogle Scholar
  56. Kwan EX, Foss EJ, Tsuchiyama S, Alvino GM, Kruglyak L, Kaeberlein M, Raghuraman MK, Brewer BJ, Kennedy BK, Bedalov A (2013) A natural polymorphism in rDNA replication origins links origin activation with calorie restriction and lifespan. PLoS Genet 9:e1003329PubMedCentralCrossRefPubMedGoogle Scholar
  57. Kwan EX, Wang XS, Amemiya HM, Brewer BJ, Raghuraman MK (2016) rDNA copy number variants are frequent passenger mutations in Saccharomyces cerevisiae deletion collections and de novo transformants. G3 (Bethesda) 6:2829–2838CrossRefGoogle Scholar
  58. Larson K, Yan SJ, Tsurumi A, Liu J, Zhou J, Gaur K, Guo D, Eickbush TH, Li WX (2012) Heterochromatin formation promotes longevity and represses ribosomal RNA synthesis. PLoS Genet 8:e1002473PubMedCentralCrossRefPubMedGoogle Scholar
  59. Lewis EB (1952) The pseudoallelism of white and apricot in Drosophila melanogaster. Proc Natl Acad Sci U S A 38:953–961PubMedCentralCrossRefPubMedGoogle Scholar
  60. Lindstrom MS, Jurada D, Bursac S, Orsolic I, Bartek J et al (2018) Nucleolus as an emerging hub in maintenance of genome stability and cancer pathogenesis. Oncogene 37:2351–2366PubMedCentralCrossRefPubMedGoogle Scholar
  61. Long EO, Dawid IB (1980) Repeated genes in eukaryotes. Annu Rev Biochem 49:727–764CrossRefGoogle Scholar
  62. Lu KL, Nelson JO, Watase GJ, Warsinger-Pepe N, Yamashita YM (2018) Transgenerational dynamics of rDNA copy number in Drosophila male germline stem cells. Elife 7Google Scholar
  63. Lyckegaard EM, Clark AG (1989) Ribosomal DNA and stellate gene copy number variation on the Y chromosome of Drosophila melanogaster. Proc Natl Acad Sci U S A 86:1944–1948PubMedCentralCrossRefPubMedGoogle Scholar
  64. Maina MB, Bailey LJ, Wagih S, Biasetti L, Pollack SJ, Quinn JP, Thorpe JR, Doherty AJ, Serpell LC (2018) The involvement of tau in nucleolar transcription and the stress response. Acta Neuropathol Commun 6:70PubMedCentralCrossRefPubMedGoogle Scholar
  65. Malinovskaya EM, Ershova ES, Golimbet VE, Porokhovnik LN, Lyapunova NA, Kutsev SI, Veiko NN, Kostyuk SV (2018) Copy number of human ribosomal genes with aging: unchanged mean, but narrowed range and decreased variance in elderly group. Front Genet 9:306PubMedCentralCrossRefPubMedGoogle Scholar
  66. Manikkam M, Guerrero-Bosagna C, Tracey R, Haque MM, Skinner MK (2012) Transgenerational actions of environmental compounds on reproductive disease and identification of epigenetic biomarkers of ancestral exposures. PLoS One 7:e31901PubMedCentralCrossRefPubMedGoogle Scholar
  67. Mather K (1944) The genetical activity of heterochromatin. Proc R Soc B 132:308–332CrossRefGoogle Scholar
  68. McStay B, Grummt I (2008) The epigenetics of rRNA genes: from molecular to chromosome biology. Annu Rev Cell Dev Biol 24:131–157CrossRefGoogle Scholar
  69. Michel AH, Kornmann B, Dubrana K, Shore D (2005) Spontaneous rDNA copy number variation modulates Sir2 levels and epigenetic gene silencing. Genes Dev 19:1199–1210PubMedCentralCrossRefPubMedGoogle Scholar
  70. Montacie C, Durut N, Opsomer A, Palm D, Comella P et al (2017) Nucleolar proteome analysis and proteasomal activity assays reveal a link between nucleolus and 26S proteasome in a. thaliana. Front Plant Sci 8:1815PubMedCentralCrossRefPubMedGoogle Scholar
  71. Muller HJ (1932) Further studies on the nature and causes of gene mutations. Proceedings of the 6th International Congress of Genetics: 213–255Google Scholar
  72. Nunez Villacis L, Wong MS, Ferguson LL, Hein N, George AJ et al (2018) New roles for the nucleolus in health and disease. Bioessays 40:e1700233CrossRefGoogle Scholar
  73. Ost A, Lempradl A, Casas E, Weigert M, Tiko T et al (2014) Paternal diet defines offspring chromatin state and intergenerational obesity. Cell 159:1352–1364CrossRefGoogle Scholar
  74. Padmanabhan N, Jia D, Geary-Joo C, Wu X, Ferguson-Smith AC, Fung E, Bieda MC, Snyder FF, Gravel RA, Cross JC, Watson ED (2013) Mutation in folate metabolism causes epigenetic instability and transgenerational effects on development. Cell 155:81–93CrossRefGoogle Scholar
  75. Paredes S, Maggert KA (2009a) Expression of I-CreI endonuclease generates deletions within the rDNA of Drosophila. Genetics 181:1661–1671PubMedCentralCrossRefPubMedGoogle Scholar
  76. Paredes S, Maggert KA (2009b) Ribosomal DNA contributes to global chromatin regulation. Proc Natl Acad Sci U S A 106:17829–17834PubMedCentralCrossRefPubMedGoogle Scholar
  77. Paredes S, Branco AT, Hartl DL, Maggert KA, Lemos B (2011) Ribosomal DNA deletions modulate genome-wide gene expression: “rDNA-sensitive” genes and natural variation. PLoS Genet 7:e1001376PubMedCentralCrossRefPubMedGoogle Scholar
  78. Paredes S, Angulo-Ibanez M, Tasselli L, Carlson SM, Zheng W, Li TM, Chua KF (2018) The epigenetic regulator SIRT7 guards against mammalian cellular senescence induced by ribosomal DNA instability. J Biol Chem 293:11242–11250PubMedCentralCrossRefPubMedGoogle Scholar
  79. Parks MM, Kurylo CM, Dass RA, Bojmar L, Lyden D, Vincent CT, Blanchard SC (2018) Variant ribosomal RNA alleles are conserved and exhibit tissue-specific expression. Sci Adv 4:eaao0665PubMedCentralCrossRefPubMedGoogle Scholar
  80. Pendle AF, Clark GP, Boon R, Lewandowska D, Lam YW, Andersen J, Mann M, Lamond AI, Brown JWS, Shaw PJ (2005) Proteomic analysis of the Arabidopsis nucleolus suggests novel nucleolar functions. Mol Biol Cell 16:260–269PubMedCentralCrossRefPubMedGoogle Scholar
  81. Peng JC, Karpen GH (2007) H3K9 methylation and RNA interference regulate nucleolar organization and repeated DNA stability. Nat Cell Biol 9:25–35CrossRefGoogle Scholar
  82. Peng JC, Karpen GH (2008) Epigenetic regulation of heterochromatic DNA stability. Curr Opin Genet Dev 18:204–211PubMedCentralCrossRefPubMedGoogle Scholar
  83. Pineiro D, Stoneley M, Ramakrishna M, Alexandrova J, Dezi V et al. (2018) Identification of the RNA polymerase I-RNA interactome. Nucleic Acids ResGoogle Scholar
  84. Pontes O, Lawrence RJ, Neves N, Silva M, Lee JH, Chen ZJ, Viegas W, Pikaard CS (2003) Natural variation in nucleolar dominance reveals the relationship between nucleolus organizer chromatin topology and rRNA gene transcription in Arabidopsis. Proc Natl Acad Sci U S A 100:11418–11423PubMedCentralCrossRefPubMedGoogle Scholar
  85. Preuss S, Pikaard CS (2007) rRNA gene silencing and nucleolar dominance: insights into a chromosome-scale epigenetic on/off switch. Biochim Biophys Acta 1769:383–392PubMedCentralCrossRefPubMedGoogle Scholar
  86. Prokopowich CD, Gregory TR, Crease TJ (2003) The correlation between rDNA copy number and genome size in eukaryotes. Genome 46:48–50CrossRefGoogle Scholar
  87. Rasooly RS, Robbins LG (1991) Rex and a suppressor of Rex are repeated neomorphic loci in the Drosophila melanogaster ribosomal DNA. Genetics 129:119–132PubMedCentralPubMedGoogle Scholar
  88. Remely M, Stefanska B, Lovrecic L, Magnet U, Haslberger AG (2015) Nutriepigenomics: the role of nutrition in epigenetic control of human diseases. Curr Opin Clin Nutr Metab Care 18:328–333CrossRefGoogle Scholar
  89. Ritossa F (1973) Crossing-over between X AND Y chromosomes during ribosomal DNA magnification in Drosophila melanogaster. Proc Natl Acad Sci U S A 70:1950–1954PubMedCentralCrossRefPubMedGoogle Scholar
  90. Ritossa FM, Atwood KC, Spiegelman S (1966) A molecular explanation of the bobbed mutants of Drosophila as partial deficiencies of “ribosomal” DNA. Genetics 54:819–834PubMedCentralPubMedGoogle Scholar
  91. Roche B, Arcangioli B, Martienssen R (2017) New roles for Dicer in the nucleolus and its relevance to cancer. Cell Cycle 16:1643–1653PubMedCentralCrossRefPubMedGoogle Scholar
  92. Salim D, Bradford WD, Freeland A, Cady G, Wang J, Pruitt SC, Gerton JL (2017) DNA replication stress restricts ribosomal DNA copy number. PLoS Genet 13:e1007006PubMedCentralCrossRefPubMedGoogle Scholar
  93. Sanchez JC, Kwan EX, Pohl TJ, Amemiya HM, Raghuraman MK, Brewer BJ (2017) Defective replication initiation results in locus specific chromosome breakage and a ribosomal RNA deficiency in yeast. PLoS Genet 13:e1007041PubMedCentralCrossRefPubMedGoogle Scholar
  94. Sanij E, Poortinga G, Sharkey K, Hung S, Holloway TP, Quin J, Robb E, Wong LH, Thomas WG, Stefanovsky V, Moss T, Rothblum L, Hannan KM, McArthur GA, Pearson RB, Hannan RD (2008) UBF levels determine the number of active ribosomal RNA genes in mammals. J Cell Biol 183:1259–1274PubMedCentralCrossRefPubMedGoogle Scholar
  95. Schawalder J, Paric E, Neff NF (2003) Telomere and ribosomal DNA repeats are chromosomal targets of the bloom syndrome DNA helicase. BMC Cell Biol 4:15PubMedCentralCrossRefPubMedGoogle Scholar
  96. Schneeberger RG, Cullis CA (1991) Specific DNA alterations associated with the environmental induction of heritable changes in flax. Genetics 128:619–630PubMedCentralPubMedGoogle Scholar
  97. Seong KH, Li D, Shimizu H, Nakamura R, Ishii S (2011) Inheritance of stress-induced, ATF-2-dependent epigenetic change. Cell 145:1049–1061CrossRefGoogle Scholar
  98. Sinclair DA, Guarente L (1997) Extrachromosomal rDNA circles--a cause of aging in yeast. Cell 91:1033–1042CrossRefGoogle Scholar
  99. Small C, Ramroop J, Otazo M, Huang LH, Saleque S, Govind S (2014) An unexpected link between notch signaling and ROS in restricting the differentiation of hematopoietic progenitors in Drosophila. Genetics 197:471–483CrossRefGoogle Scholar
  100. Specchia V, Piacentini L, Tritto P, Fanti L, D'Alessandro R et al (2010) Hsp90 prevents phenotypic variation by suppressing the mutagenic activity of transposons. Nature 463:662–665CrossRefGoogle Scholar
  101. Spofford JB (1976) Position-effect variegation in Drosophila, pp. 955–1019 in The genetics and biology of Drosophila, edited by M. Ashburner and E. Novitski. Academic PressGoogle Scholar
  102. Spofford JB, DeSalle R (1991) Nucleolus organizer-suppressed position-effect variegation in Drosophila melanogaster. Genet Res 57:245–255CrossRefGoogle Scholar
  103. Sriskanthadevan-Pirahas S, Lee J, Grewal SS (2018) The EGF/Ras pathway controls growth in Drosophila via ribosomal RNA synthesis. Dev Biol 439:19–29CrossRefGoogle Scholar
  104. Stults DM, Killen MW, Pierce HH, Pierce AJ (2008) Genomic architecture and inheritance of human ribosomal RNA gene clusters. Genome Res 18:13–18PubMedCentralCrossRefPubMedGoogle Scholar
  105. Stults DM, Killen MW, Williamson EP, Hourigan JS, Vargas HD, Arnold SM, Moscow JA, Pierce AJ (2009) Human rRNA gene clusters are recombinational hotspots in cancer. Cancer Res 69:9096–9104CrossRefGoogle Scholar
  106. Sun W, Samimi H, Gamez M, Zare H, Frost B (2018) Pathogenic tau-induced piRNA depletion promotes neuronal death through transposable element dysregulation in neurodegenerative tauopathies. Nat Neurosci 21:1038–1048CrossRefGoogle Scholar
  107. Tartof KD (1973) Regulation of ribosomal RNA gene multiplicity in Drosophila melanogaster. Genetics 73:57–71PubMedCentralPubMedGoogle Scholar
  108. Tartof KD (1974) Unequal mitotic sister chromatid exchange and disproportionate replication as mechanisms regulating ribosomal RNA gene redundancy. Cold Spring Harb Symp Quant Biol 38:491–500CrossRefGoogle Scholar
  109. Terracol R, Prud'homme N (1981) 26S and 18S rRNA synthesis in bobbed mutants of Drosophila melanogaster. Biochimie 63:451–455CrossRefGoogle Scholar
  110. Terracol R, Prud'homme N (1986) Differential elimination of rDNA genes in bobbed mutants of Drosophila melanogaster. Mol Cell Biol 6:1023–1031PubMedCentralCrossRefPubMedGoogle Scholar
  111. Terracol R, Iturbide Y, Prud'Homme N (1990) Partial reversion at the bobbed locus of Drosophila melanogaster. Biol Cell 68:65–71Google Scholar
  112. Tiku V, Antebi A (2018) Nucleolar function in lifespan regulation. Trends Cell Biol 28:662–672CrossRefGoogle Scholar
  113. Tiku V, Jain C, Raz Y, Nakamura S, Heestand B et al (2017) Small nucleoli are a cellular hallmark of longevity. Nat Commun 8:16083PubMedCentralCrossRefPubMedGoogle Scholar
  114. Torrano V, Navascues J, Docquier F, Zhang R, Burke LJ et al (2006) Targeting of CTCF to the nucleolus inhibits nucleolar transcription through a poly(ADP-ribosyl)ation-dependent mechanism. J Cell Sci 119:1746–1759CrossRefGoogle Scholar
  115. Udugama M, Sanij E, Voon HPJ, Son J, Hii L, Henson JD, Chan FL, Chang FTM, Liu Y, Pearson RB, Kalitsis P, Mann JR, Collas P, Hannan RD, Wong LH (2018) Ribosomal DNA copy loss and repeat instability in ATRX-mutated cancers. Proc Natl Acad Sci U S A 115:4737–4742PubMedCentralCrossRefPubMedGoogle Scholar
  116. van de Nobelen S, Rosa-Garrido M, Leers J, Heath H, Soochit W, Joosen L, Jonkers I, Demmers J, van der Reijden M, Torrano V, Grosveld F, Delgado MD, Renkawitz R, Galjart N, Sleutels F (2010) CTCF regulates the local epigenetic state of ribosomal DNA repeats. Epigenetics Chromatin 3:19PubMedCentralCrossRefPubMedGoogle Scholar
  117. Waddington CH (1957) The strategy of the genesGoogle Scholar
  118. Waddington CH (1959) Canalization of development and genetic assimilation of acquired characters. Nature 183:1654–1655CrossRefGoogle Scholar
  119. Wang M, Lemos B (2017) Ribosomal DNA copy number amplification and loss in human cancers is linked to tumor genetic context, nucleolus activity, and proliferation. PLoS Genet 13:e1006994PubMedCentralCrossRefPubMedGoogle Scholar
  120. Wang W, Wan T, Becher H, Kuderova A, Leitch IJ, Garcia S, Leitch AR, Kovařík A (2018) Remarkable variation of ribosomal DNA organization and copy number in gnetophytes, a distinct lineage of gymnosperms. Ann BotGoogle Scholar
  121. Warmerdam DO, van den Berg J, Medema RH (2016) Breaks in the 45S rDNA Lead to recombination-mediated loss of repeats. Cell Rep 14:2519–2527CrossRefGoogle Scholar
  122. Xu B, Li H, Perry JM, Singh VP, Unruh J, Yu Z, Zakari M, McDowell W, Li L, Gerton JL (2017) Ribosomal DNA copy number loss and sequence variation in cancer. PLoS Genet 13:e1006771PubMedCentralCrossRefPubMedGoogle Scholar
  123. Youngson NA, Whitelaw E (2008) Transgenerational epigenetic effects. Annu Rev Genomics Hum Genet 9:233–257CrossRefGoogle Scholar
  124. Zhang Q, Shalaby NA, Buszczak M (2014) Changes in rRNA transcription influence proliferation and cell fate within a stem cell lineage. Science 343:298–301PubMedCentralCrossRefPubMedGoogle Scholar
  125. Zhou J, Sackton TB, Martinsen L, Lemos B, Eickbush TH, Hartl DL (2012) Y chromosome mediates ribosomal DNA silencing and modulates the chromatin state in Drosophila. Proc Natl Acad Sci U S A. CrossRefGoogle Scholar

Copyright information

© Springer Nature B.V. 2018

Authors and Affiliations

  1. 1.Department of Cellular and Molecular Medicine, College of MedicineUniversity of ArizonaTucsonUSA
  2. 2.University of Arizona Cancer CenterUniversity of Arizona College of MedicineTucsonUSA

Personalised recommendations