Active Human Nucleolar Organizer Regions are Interspersed with Inactive rDNA Repeats in Normal and Tumor Cells

References

• Lempiäinen H , ShoreD . Growth control and ribosome biogenesis . Curr. Opin. Cell Biol.21 ( 6 ), 855 – 863 ( 2009 ).
   PubMed Web of Science ®Google Scholar
• Bywater MJ , PearsonRB , McArthurGA , HannanRD . Dysregulation of the basal RNA polymerase transcription apparatus in cancer . Nat. Rev. Cancer13 ( 5 ), 299 – 314 ( 2013 ).
   PubMed Web of Science ®Google Scholar
• Caburet S , ContiC , SchurraC , LebofskyR , EdelsteinSJ , BensimonA . Human ribosomal RNA gene arrays display a broad range of palindromic structures . Genome Res.15 ( 8 ), 1079 – 1085 ( 2005 ).
   PubMed Web of Science ®Google Scholar
• McStay B , GrummtI . The epigenetics of rRNA genes: from molecular to chromosome biology . Annu. Rev. Cell Dev. Biol.24 , 131 – 157 ( 2008 ).
   PubMed Web of Science ®Google Scholar
• Guillén AKZ , HiraiY , TanoueT , HiraiH . Transcriptional repression mechanisms of nucleolus organizer regions (NORs) in humans and chimpanzees . Chromosome Res.12 ( 3 ), 225 – 237 ( 2004 ).
   PubMed Web of Science ®Google Scholar
• Drygin D , LinA , BliesathJet al. Targeting RNA polymerase I with an oral small molecule CX-5461 inhibits ribosomal RNA synthesis and solid tumor growth . Cancer Res.71 ( 4 ), 1418 – 1430 ( 2011 ).
   PubMed Web of Science ®Google Scholar
• Drygin D , RiceWG , GrummtI . The RNA polymerase I transcription machinery: an emerging target for the treatment of cancer . Annu. Rev. Pharmacol. Toxicol.50 , 131 – 156 ( 2010 ).
   PubMed Web of Science ®Google Scholar
• Bywater MJ , PoortingaG , SanijEet al. Inhibition of RNA polymerase I as a therapeutic strategy to promote cancer-specific activation of p53 . Cancer Cell22 ( 1 ), 51 – 65 ( 2012 ).
   PubMed Web of Science ®Google Scholar
• Hein N , HannanKM , GeorgeAJ , SanijE , HannanRD . The nucleolus: an emerging target for cancer therapy . Trends Mol. Med.19 ( 11 ), 643 – 654 ( 2013 ).
   PubMed Web of Science ®Google Scholar
• Peltonen K , ColisL , LiuHet al. A targeting modality for destruction of RNA polymerase I that possesses anticancer activity . Cancer Cell25 ( 1 ), 77 – 90 ( 2014 ).
   PubMed Web of Science ®Google Scholar
• Grob A , ColleranC , McStayB . Construction of synthetic nucleoli in human cells reveals how a major functional nuclear domain is formed and propagated through cell division . Genes Dev.28 ( 3 ), 220 – 230 ( 2014 ).
   PubMed Web of Science ®Google Scholar
• Hamdane N , StefanovskyVY , TremblayMGet al. Conditional inactivation of upstream binding factor reveals its epigenetic functions and the existence of a somatic nucleolar precursor body . PLoS Genet.10 ( 8 ), e1004505 ( 2014 ).
   PubMed Web of Science ®Google Scholar
• Grummt I , LängstG . Epigenetic control of RNA polymerase I transcription in mammalian cells . Biochim. Biophys. Acta1829 ( 3–4 ), 393 – 404 ( 2013 ).
   PubMed Web of Science ®Google Scholar
• Tucker S , VitinsA , PikaardCS . Nucleolar dominance and ribosomal RNA gene silencing . Curr. Opin. Cell Biol.22 ( 3 ), 351 – 356 ( 2010 ).
   PubMed Web of Science ®Google Scholar
• Sanij E , PoortingaG , SharkeyKet al. UBF levels determine the number of active ribosomal RNA genes in mammals . J. Cell Biol.183 ( 7 ), 1259 – 1274 ( 2008 ).
   PubMed Web of Science ®Google Scholar
• Németh A , LängstG . Genome organization in and around the nucleolus . Trends Genet.27 ( 4 ), 149 – 156 ( 2011 ).
   PubMed Web of Science ®Google Scholar
• Ghoshal K , MajumderS , DattaJet al. Role of human ribosomal RNA (rRNA) promoter methylation and of methyl-CpG-binding protein MBD2 in the suppression of rRNA gene expression . J. Biol. Chem.279 ( 8 ), 6783 – 6793 ( 2004 ).
   PubMed Web of Science ®Google Scholar
• Santoro R , GrummtI . Molecular mechanisms mediating methylation-dependent silencing of ribosomal gene transcription . Mol. Cell.8 ( 3 ), 719 – 725 ( 2001 ).
   PubMed Web of Science ®Google Scholar
• Stancheva I , LucchiniR , KollerT , SogoJM . Chromatin structure and methylation of rat rRNA genes studied by formaldehyde fixation and psoralen cross-linking . Nucleic Acids Res.25 ( 9 ), 1727 – 1735 ( 1997 ).
   PubMed Web of Science ®Google Scholar
• Brock GJ , BirdA . Mosaic methylation of the repeat unit of the human ribosomal RNA genes . Hum. Mol. Genet.6 ( 3 ), 451 – 456 ( 1997 ).
   PubMed Web of Science ®Google Scholar
• Németh A , GuibertS , TiwariVK , OhlssonR , LängstG . Epigenetic regulation of TTF-I-mediated promoter-terminator interactions of rRNA genes . EMBO J.27 ( 8 ), 1255 – 1265 ( 2008 ).
   PubMed Web of Science ®Google Scholar
• Pontvianne F , BlevinsT , ChandrasekharaCet al. Subnuclear partitioning of rRNA genes between the nucleolus and nucleoplasm reflects alternative epiallelic states . Genes Dev.27 ( 14 ), 1545 – 1550 ( 2013 ).
   PubMed Web of Science ®Google Scholar
• Scheer U , RoseKM . Localization of RNA polymerase I in interphase cells and mitotic chromosomes by light and electron microscopic immunocytochemistry . Proc. Natl Acad. Sci. USA81 ( 5 ), 1431 – 1435 ( 1984 ).
   PubMed Web of Science ®Google Scholar
• Roussel P , AndréC , ComaiL , Hernandez-VerdunD . The rDNA transcription machinery is assembled during mitosis in active NORs and absent in inactive NORs . J. Cell Biol.133 ( 2 ), 235 – 246 ( 1996 ).
   PubMed Web of Science ®Google Scholar
• de Capoa A , AleixandreC , FelliMPet al. Inheritance of ribosomal gene activity and level of DNA methylation of individual gene clusters in a three generation family . Hum. Genet.88 ( 2 ), 146 – 152 ( 1991 ).
   PubMed Web of Science ®Google Scholar
• Ananiev GE , GoldsteinS , RunnheimRet al. Optical mapping discerns genome wide DNA methylation profiles . BMC Mol. Biol.9 , 68 ( 2008 ).
   PubMed Web of Science ®Google Scholar
• Flusberg BA , WebsterDR , LeeJHet al. Direct detection of DNA methylation during single-molecule, real-time sequencing . Nat. Methods7 ( 6 ), 461 – 465 ( 2010 ).
   PubMed Web of Science ®Google Scholar
• Wallace EVB , StoddartD , HeronAJet al. Identification of epigenetic DNA modifications with a protein nanopore . Chem. Commun.46 ( 43 ), 8195 – 8197 ( 2010 ).
   PubMed Web of Science ®Google Scholar
• Cipriany BR , ZhaoR , MurphyPJet al. Single molecule epigenetic analysis in a nanofluidic channel . Anal. Chem.82 ( 6 ), 2480 – 2487 ( 2010 ).
   PubMed Web of Science ®Google Scholar
• Cerf A , CiprianyBR , BenítezJJ , CraigheadHG . Single DNA molecule patterning for high-throughput epigenetic mapping . Anal. Chem.83 ( 21 ), 8073 – 8077 ( 2011 ).
   PubMed Web of Science ®Google Scholar
• Cipriany BR , MurphyPJ , HagarmanJAet al. Real-time analysis and selection of methylated DNA by fluorescence-activated single molecule sorting in a nanofluidic channel . Proc. Natl Acad. Sci. USA109 ( 22 ), 8477 – 8482 ( 2012 ).
   PubMed Web of Science ®Google Scholar
• Murphy PJ , CiprianyBR , WallinCBet al. Single-molecule analysis of combinatorial epigenomic states in normal and tumor cells . Proc. Natl Acad. Sci. USA110 ( 19 ), 7772 – 7777 ( 2013 ).
   PubMed Web of Science ®Google Scholar
• Zillner K , NémethA . Single-molecule, genome-scale analyses of DNA modifications: exposing the epigenome with next-generation technologies . Epigenomics4 ( 4 ), 403 – 414 ( 2012 ).
   PubMed Web of Science ®Google Scholar
• Aguilar CA , CraigheadHG . Micro- and nanoscale devices for the investigation of epigenetics and chromatin dynamics . Nat. Nanotechnol.8 ( 10 ), 709 – 718 ( 2013 ).
   PubMed Web of Science ®Google Scholar
• Levy-Sakin M , EbensteinY . Beyond sequencing: optical mapping of DNA in the age of nanotechnology and nanoscopy . Curr. Opin. Biotechnol.24 ( 4 ), 690 – 698 ( 2013 ).
   PubMed Web of Science ®Google Scholar
• Schurra C , BensimonA . Combing genomic DNA for structural and functional studies . Methods Mol. Biol.464 , 71 – 90 ( 2009 ).
   PubMedGoogle Scholar
• Németh A . Methyl-combing: single-molecule analysis of DNA methylation on stretched DNA fibers . Methods Mol. Biol.1094 , 233 – 241 ( 2014 ).
   PubMedGoogle Scholar
• Bensimon A , SimonA , ChiffaudelA , CroquetteV , HeslotF , BensimonD . Alignment and sensitive detection of DNA by a moving interface . Science265 ( 5181 ), 2096 – 2098 ( 1994 ).
   PubMed Web of Science ®Google Scholar
• Horard B , EymeryA , FourelGet al. Global analysis of DNA methylation and transcription of human repetitive sequences . Epigenetics4 ( 5 ), 339 – 350 ( 2009 ).
   PubMed Web of Science ®Google Scholar
• de Koning APJ , GuW , CastoeTA , BatzerMA , PollockDD . Repetitive elements may comprise over two-thirds of the human genome . PLoS Genet.7 ( 12 ), e1002384 ( 2011 ).
   PubMed Web of Science ®Google Scholar
• Ross JP , RandKN , MolloyPL . Hypomethylation of repeated DNA sequences in cancer . Epigenomics2 ( 2 ), 245 – 269 ( 2010 ).
   PubMed Web of Science ®Google Scholar
• Floutsakou I , AgrawalS , NguyenTT , SeoigheC , GanleyARD , McStayB . The shared genomic architecture of human nucleolar organizer regions . Genome Res.23 ( 12 ), 2003 – 2012 ( 2013 ).
   PubMed Web of Science ®Google Scholar
• Espada J , BallestarE , SantoroRet al. Epigenetic disruption of ribosomal RNA genes and nucleolar architecture in DNA methyltransferase 1 (Dnmt1) deficient cells . Nucleic Acids Res.35 ( 7 ), 2191 – 2198 ( 2007 ).
   PubMed Web of Science ®Google Scholar
• Gagnon-Kugler T , LangloisF , StefanovskyV , LessardF , MossT . Loss of human ribosomal gene CpG methylation enhances cryptic RNA polymerase II transcription and disrupts ribosomal RNA processing . Mol. Cell35 ( 4 ), 414 – 425 ( 2009 ).
   PubMed Web of Science ®Google Scholar
• Stults DM , KillenMW , WilliamsonEPet al. Human rRNA gene clusters are recombinational hotspots in cancer . Cancer Res.69 ( 23 ), 9096 – 9104 ( 2009 ).
   PubMed Web of Science ®Google Scholar
• Killen MW , StultsDM , AdachiN , HanakahiL , PierceAJ . Loss of Bloom syndrome protein destabilizes human gene cluster architecture . Hum. Mol. Genet.18 ( 18 ), 3417 – 3428 ( 2009 ).
   PubMed Web of Science ®Google Scholar
• Law JA , JacobsenSE . Establishing, maintaining and modifying DNA methylation patterns in plants and animals . Nat. Rev. Genet.11 ( 3 ), 204 – 220 ( 2010 ).
   PubMed Web of Science ®Google Scholar