Noncoding RNAs in Long-Term Memory Formation

Abstract

Current research exploring the molecular basis of memory focuses mainly on proteins despite recent genomic studies reporting the abundant transcription of non-protein-coding RNA (ncRNA). Although ncRNAs are involved in a diverse range of biological processes, they are particularly prevalent within the nervous system, where they contribute towards the complexity and function of the mammalian brain. In this review, we apply recent advances in ncRNA biology to predict a critical role for ncRNAs in the molecular mechanisms underlying memory formation and maintenance. We describe the role of ncRNAs in regulating the translation, stability, and editing of mRNA populations in response to synaptic activity during memory formation and the role of ncRNAs in the epigenetic and transcriptional programs that underlie long-term memory storage. We also consider ncRNAs acting as an additional avenue of communication between neurons by their intercellular trafficking. Taken together, the emerging evidence suggests a central role for ncRNAs in memory formation and provokes novel research directions in this field. NEUROSCIENTIST 14(5):434—445, 2008. DOI: 10.1177/1073858408319187

Keywords

long-term potentiation synaptic plasticity microRNAs neuron intercellular signaling

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References

Abarrategui I. , Krangel MS 2007. Noncoding transcription controls downstream promoters to regulate T-cell receptor alpha recombination. Embo J 26(20):4380-90.

Abeliovich A. , Gerber D. , Tanaka O. , Katsuki M. , Graybiel AM , Tonegawa S. 1992. On somatic recombination in the central nervous system of transgenic mice. Science 257(5068):404-10.

Amaral PP , Dinger ME , Mercer TR , Mattick JS 2008. The eukaryotic genome as an RNA machine. Science. 319(5871):1787-9.

Andersen BB , Gundersen HJ , Pakkenberg B. 2003. Aging of the human cerebellum: a stereological study. J Comp Neurol 466(3):356-65.

Anderson P. , Kedersha N. 2006. RNA granules. J Cell Biol 172(6): 803-8.

Ashraf SI , McLoon AL , Sclarsic SM , Kunes S. 2006. Synaptic protein synthesis associated with memory is regulated by the RISC pathway in Drosophila. Cell 124(1):191-205.

Athanasiadis A. , Rich A. , Maas S. 2004. Widespread A-to-I RNA editing of Alu-containing mRNAs in the human transcriptome. PLoS Biol 2(12):e391.

Barbee SA , Estes PS , Cziko AM , Hillebrand J. , Luedeman RA , Coller JM , and others. 2006. Staufen- and FMRP-containing neuronal RNPs are structurally and functionally related to somatic P bodies. Neuron 52(6):997-1009.

Barco A. , Bailey CH , Kandel ER 2006. Common molecular mechanisms in explicit and implicit memory . J Neurochem 97(6):1520-33.

10.

Barlati S. , Barbon A. 2005. RNA editing: a molecular mechanism for the fine modulation of neuronal transmission. Acta Neurochir Suppl 93:53-7.

11.

Bartel DP 2004. MicroRNAs: genomics, biogenesis, mechanism, and function . Cell 116(2):281-97.

12.

Bernstein E. , Allis CD 2005. RNA meets chromatin. Genes Dev 19(14): 1635-55.

13.

Blow M. , Futreal PA , Wooster R. , Stratton MR 2004. A survey of RNA editing in human brain. Genome Res 14(12):2379-87.

14.

Blow MJ , Grocock RJ , van Dongen S. , Enright AJ , Dicks E. , Futreal PA , and others. 2006. RNA editing of human microRNAs. Genome Biol 7(4):R27.

15.

Bourtchuladze R. , Frenguelli B. , Blendy J. , Cioffi D. , Schutz G. , Silva AJ 1994. Deficient long-term memory in mice with a targeted mutation of the cAMP-responsive element-binding protein. Cell 79(1):59-68.

16.

Bramham CR , Wells DG 2007. Dendritic mRNA: transport, translation and function . Nat Rev Neurosci 8(10):776-89.

17.

Calabrese JM , Seila AC , Yeo GW , Sharp PA 2007. RNA sequence analysis defines Dicer's role in mouse embryonic stem cells. Proc Natl Acad Sci U S A 104(46):18097-102.

18.

Cavallaro S. , D'Agata V. , Manickam P. , Dufour F. , Alkon DL 2002. Memory-specific temporal profiles of gene expression in the hippocampus. Proc Natl Acad Sci U S A 99(25):16279-84.

19.

Cawley S. , Bekiranov S. , Ng HH , Kapranov P. , Sekinger EA , Kampa D. , and others. 2004. Unbiased mapping of transcription factor binding sites along human chromosomes 21 and 22 points to widespread regulation of noncoding RNAs. Cell 116(4):499-509.

20.

Centonze D. , Rossi S. , Napoli I. , Mercaldo V. , Lacoux C. , Ferrari F. , and others. 2007. The brain cytoplasmic RNA BC1 regulates dopamine D2 receptor-mediated transmission in the striatum. J Neurosci 27(33):8885-92.

21.

Chen BL , Hall DH , Chklovskii DB 2006. Wiring optimization can relate neuronal structure and function. Proc Natl Acad Sci U S A 103(12):4723-8.

22.

Chen CX , Cho DS , Wang Q. , Lai F. , Carter KC , Nishikura K. 2000. A third member of the RNA-specific adenosine deaminase gene family, ADAR3, contains both single- and double-stranded RNA binding domains. RNA 6(5):755-67.

23.

Conaco C. , Otto S. , Han JJ , Mandel G. 2006. Reciprocal actions of REST and a microRNA promote neuronal identity. Proc Natl Acad Sci U S A 103(7):2422-7.

24.

Cox LJ , Hengst U. , Gurskaya NG , Lukyanov KA , Jaffrey SR 2008. Intra-axonal translation and retrograde trafficking of CREB promotes neuronal survival. Nat Cell Biol 10(2):149-59.

25.

Dash PK , Hochner B. , Kandel ER 1990. Injection of the cAMP-responsive element into the nucleus of Aplysia sensory neurons blocks long-term facilitation. Nature 345(6277):718-21.

26.

Dinger ME , Mercer TR , Mattick JS 2008. RNAs as extracellular signaling molecules. J Mol Endocrinol 40(4):151-9.

27.

Dubnau J. , Chiang AS , Grady L. , Barditch J. , Gossweiler S. , McNeil J. , and others. 2003. The staufen/pumilio pathway is involved in Drosophila long-term memory. Curr Biol 13(4):286-96.

28.

Eisenberg E. , Nemzer S. , Kinar Y. , Sorek R. , Rechavi G. , Levanon EY 2005. Is abundant A-to-I RNA editing primate-specific ? Trends Genet 21(2):77-81.

29.

Engstrom PG , Suzuki H. , Ninomiya N. , Akalin A. , Sessa L. , Lavorgna G. , and others. 2006. Complex loci in human and mouse genomes . PLoS Genet 2(4):e47.

30.

Eyman M. , Cefaliello C. , Ferrara E. , De Stefano R. , Lavina ZS , Crispino M. , and others. 2007. Local synthesis of axonal and presynaptic RNA in squid model systems. Eur J Neurosci 25(2):341-50.

31.

Faure J. , Lachenal G. , Court M. , Hirrlinger J. , Chatellard-Causse C. , Blot B. , and others. 2006. Exosomes are released by cultured cortical neurones. Mol Cell Neurosci 31(4):642-8.

32.

Feinberg EH , Hunter CP 2003. Transport of dsRNA into cells by the transmembrane protein SID-1. Science 301(5639):1545-7.

33.

Feng J. , Bi C. , Clark BS , Mady R. , Shah P. , Kohtz JD 2006. The Evf-2 noncoding RNA is transcribed from the Dlx-5/6 ultraconserved region and functions as a Dlx-2 transcriptional coactivator . Genes Dev 20(11):1470-84.

34.

Frey U. , Krug M. , Reymann KG , Matthies H. 1988. Anisomycin, an inhibitor of protein synthesis, blocks late phases of LTP phenomena in the hippocampal CA1 region in vitro . Brain Res 452(1-2):57-65.

35.

Frey U. , Morris RG 1998. Synaptic tagging: implications for late maintenance of hippocampal long-term potentiation. Trends Neurosci 21(5):181-8.

36.

Gabory A. , Ripoche MA , Yoshimizu T. , Dandolo L. 2006. The H19 gene: regulation and function of a non-coding RNA. Cytogenet Genome Res 113(1-4):188-93.

37.

Gerhard DS , Wagner L. , Feingold EA , Shenmen CM , Grouse LH , Schuler G. , and others. 2004. The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC). Genome Res 14(10B):2121-7.

38.

Girard A. , Sachidanandam R. , Hannon GJ , Carmell MA 2006. A germline-specific class of small RNAs binds mammalian Piwi proteins. Nature 442(7099):199-202.

39.

Goelet P. , Castellucci VF , Schacher S. , Kandel ER 1986. The long and the short of long-term memory-a molecular framework. Nature 322(6078):419-22.

40.

Goodstadt L. , Ponting CP 2006. Phylogenetic reconstruction of orthology, paralogy, and conserved synteny for dog and human. PLoS Comput Biol 2(9):e133.

41.

Guzowski JF , McGaugh JL 1997. Antisense oligodeoxynucleotidemediated disruption of hippocampal cAMP response element binding protein levels impairs consolidation of memory for water maze training. Proc Natl Acad Sci U S A 94(6):2693-8.

42.

Hatada I. , Morita S. , Obata Y. , Sotomaru Y. , Shimoda M. , Kono T. 2001. Identification of a new imprinted gene, Rian, on mouse chromosome 12 by fluorescent differential display screening. J Biochem (Tokyo) 130(2):187-90.

43.

Impey S. , McCorkle SR , Cha-Molstad H. , Dwyer JM , Yochum GS , Boss JM , and others. 2004. Defining the CREB regulon: a genome-wide analysis of transcription factor regulatory regions. Cell 119(7): 1041-54.

44.

Kanai Y. , Dohmae N. , Hirokawa N. 2004. Kinesin transports RNA: isolation and characterization of an RNA-transporting granule. Neuron 43(4):513-25.

45.

Kanellopoulou C. , Muljo SA , Kung AL , Ganesan S. , Drapkin R. , Jenuwein T. , and others. 2005. Dicer-deficient mouse embryonic stem cells are defective in differentiation and centromeric silencing. Genes Dev 19(4):489-501.

46.

Kapranov P. , Cheng J. , Dike S. , Nix DA , Duttagupta R. , Willingham AT , and others. 2007. RNA maps reveal new RNA classes and a possible function for pervasive transcription. Science 316(5830):1484-8.

47.

Kawahara Y. , Zinshteyn B. , Sethupathy P. , Iizasa H. , Hatzigeorgiou AG , Nishikura K. 2007. Redirection of silencing targets by adenosine-to-inosine editing of miRNAs. Science 315(5815):1137-40.

48.

Kennedy MJ , Ehlers MD 2006. Organelles and trafficking machinery for postsynaptic plasticity. Annu Rev Neurosci 29:325-62.

49.

Kishore S. , Stamm S. 2006. The snoRNA HBII-52 regulates alternative splicing of the serotonin receptor 2C. Science 311(5758):230-2.

50.

Kiss T. 2002. Small nucleolar RNAs: an abundant group of noncoding RNAs with diverse cellular functions. Cell 109(2):145-8.

51.

Kobayashi S. , Takashima A. , Anzai K. 1998. The dendritic translocation of translin protein in the form of BC1 RNA protein particles in developing rat hippocampal neurons in primary culture. Biochem Biophys Res Commun 253(2):448-53.

52.

Kosik KS 2006. The neuronal microRNA system. Nat Rev Neurosci 7(12):911-20.

53.

Krichevsky AM , Kosik KS 2001. Neuronal RNA granules: a link between RNA localization and stimulation-dependent translation. Neuron 32(4):683-96.

54.

Kuwabara T. , Hsieh J. , Nakashima K. , Taira K. , Gage FH 2004. A small modulatory dsRNA specifies the fate of adult neural stem cells. Cell 116(6):779-93.

55.

Kye MJ , Liu T. , Levy SF , Xu NL , Groves BB , Bonneau R. , and others. 2007. Somatodendritic microRNAs identified by laser capture and multiplex RT-PCR. RNA 13(8):1224-34.

56.

Landgraf P. , Rusu M. , Sheridan R. , Sewer A. , Iovino N. , Aravin A. , and others. 2007. A mammalian microRNA expression atlas based on small RNA library sequencing. Cell 129(7):1401-14.

57.

Lau NC , Seto AG , Kim J. , Kuramochi-Miyagawa S. , Nakano T. , Bartel DP , and others. 2006. Characterization of the piRNA complex from rat testes. Science 313(5785):363-7.

58.

Lein ES , Hawrylycz MJ , Ao N. , Ayres M. , Bensinger A. , Bernard A. , and others. 2007. Genome-wide atlas of gene expression in the adult mouse brain. Nature 445(7124):168-76.

59.

Levanon EY , Eisenberg E. , Yelin R. , Nemzer S. , Hallegger M. , Shemesh R. , and others. 2004. Systematic identification of abundant A-to-I editing sites in the human transcriptome. Nat Biotechnol 22(8):1001-5.

60.

Levenson JM , Sweatt JD 2005. Epigenetic mechanisms in memory formation. Nat Rev Neurosci 6(2):108-18.

61.

Levenson JM , Sweatt JD 2006. Epigenetic mechanisms: a common theme in vertebrate and invertebrate memory formation. Cell Mol Life Sci 63(9):1009-16.

62.

Lewejohann L. , Skryabin BV , Sachser N. , Prehn C. , Heiduschka P. , Thanos S. , and others. 2004. Role of a neuronal small non-messenger RNA: behavioural alterations in BC1 RNA-deleted mice. Behav Brain Res 154(1):273-89.

63.

Lim LP , Lau NC , Garrett-Engele P. , Grimson A. , Schelter JM , Castle J. , and others. 2005. Microarray analysis shows that some microRNAs down-regulate large numbers of target mRNAs. Nature 433(7027):769-73.

64.

Lynch MA 2004. Long-term potentiation and memory. Physiol Rev 84(1):87-136.

65.

Macbeth MR , Schubert HL , Vandemark AP , Lingam AT , Hill CP , Bass BL 2005. Inositol hexakisphosphate is bound in the ADAR2 core and required for RNA editing. Science 309(5740):1534-9.

66.

Makeyev EV , Zhang J. , Carrasco MA , Maniatis T. 2007. The MicroRNA miR-124 promotes neuronal differentiation by triggering brain-specific alternative pre-mRNA splicing. Mol Cell 27(3):435-48.

67.

Mariner PD , Walters RD , Espinoza CA , Drullinger LF , Wagner SD , Kugel JF , and others. 2008. Human Alu RNA is a modular transacting repressor of mRNA transcription during heat shock. Mol Cell 29(4):499-509.

68.

Martin KC , Kosik KS 2002. Synaptic tagging-who's it? Nat Rev Neurosci 3(10):813-20.

69.

Mattick JS 2007. A new paradigm for developmental biology. J Exp Biol 210(Pt 9):1526-47.

70.

Mattick JS , Makunin IV 2006. Non-coding RNA. Hum Mol Genet 15(Spec No 1):R17-29.

71.

Mattick JS , Mehler MF 2008. RNA editing, DNA recoding and the evolution of human cognition . Trends Neurosci. 31(5):227-33.

72.

Mehler MF , Mattick JS 2006. Non-coding RNAs in the nervous system. J Physiol 575(Pt 2):333-41.

73.

Mehler MF , Mattick JS 2007. Noncoding RNAs and RNA editing in brain development, functional diversification, and neurological disease. Physiol Rev 87(3):799-823.

74.

Mercer TR , Dinger ME , Sunkin SM , Mehler MF , Mattick JS 2008. Specific expression of long noncoding RNAs in the mouse brain. Proc Natl Acad Sci U S A 105(2):716-21.

75.

Miller CA , Sweatt JD 2007. Covalent modification of DNA regulates memory formation . Neuron 53(6):857-69.

76.

Mineno J. , Okamoto S. , Ando T. , Sato M. , Chono H. , Izu H. , and others. 2006. The expression profile of microRNAs in mouse embryos. Nucleic Acids Res 34(6):1765-71.

77.

Mizuno K. , Antunes-Martins A. , Ris L. , Peters M. , Godaux E. , Giese KP 2007. Calcium/calmodulin kinase kinase beta has a male-specific role in memory formation. Neuroscience 145(2):393-402.

78.

Montarolo PG , Goelet P. , Castellucci VF , Morgan J. , Kandel ER , Schacher S. 1986. A critical period for macromolecular synthesis in long-term heterosynaptic facilitation in Aplysia. Science 234(4781):1249-54.

79.

Muller U. , Carew TJ 1998. Serotonin induces temporally and mechanistically distinct phases of persistent PKA activity in Aplysia sensory neurons. Neuron 21(6):1423-34.

80.

Muotri AR , Gage FH 2006. Generation of neuronal variability and complexity. Nature 441(7097):1087-93.

81.

Murashov AK , Chintalgattu V. , Islamov RR , Lever TE , Pak ES , Sierpinski PL , and others. 2007. RNAi pathway is functional in peripheral nerve axons. Faseb J 21(3):656-70.

82.

Nowacki M. , Vijayan V. , Zhou Y. , Schotanus K. , Doak TG , Landweber LF 2007. RNA-mediated epigenetic programming of a genome-rearrangement pathway. Nature 451(7175):153-8.

83.

Ogryzko VV , Schiltz RL , Russanova V. , Howard BH , Nakatani Y. 1996. The transcriptional coactivators p300 and CBP are histone acetyl-transferases. Cell 87(5):953-9.

84.

Okamoto I. , Arnaud D. , Le Baccon P. , Otte AP , Disteche CM , Avner P. , and others. 2005. Evidence for de novo imprinted X-chromosome inactivation independent of meiotic inactivation in mice. Nature 438(7066):369-73.

85.

Okazaki Y. , Furuno M. , Kasukawa T. , Adachi J. , Bono H. , Kondo S. , and others. 2002. Analysis of the mouse transcriptome based on functional annotation of 60,770 full-length cDNAs. Nature 420(6915): 563-73.

86.

Park CS , Gong R. , Stuart J. , Tang SJ 2006. Molecular network and chromosomal clustering of genes involved in synaptic plasticity in the hippocampus. J Biol Chem 281(40):30195-211.

87.

Pennisi E. 2007. Genetics. Working the (gene count) numbers: finally, a firm answer? Science 316(5828):1113.

88.

Pikaard CS 2006. Cell biology of the Arabidopsis nuclear siRNA pathway for RNA-directed chromatin modification. Cold Spring Harb Symp Quant Biol 71:473-80.

89.

Place RF , Li LC , Pookot D. , Noonan EJ , Dahiya R. 2008. MicroRNA-373 induces expression of genes with complementary promoter sequences. Proc Natl Acad Sci U S A 105(5):1608-13.

90.

Ponjavic J. , Ponting CP , Lunter G. 2007. Functionality or transcriptional noise? Evidence for selection within long noncoding RNAs. Genome Res 17(5):556-65.

91.

Prasanth KV , Spector DL 2007. Eukaryotic regulatory RNAs: an answer to the `genome complexity' conundrum. Genes Dev 21(1):11-42.

92.

Ratajczak J. , Miekus K. , Kucia M. , Zhang J. , Reca R. , Dvorak P. , and others. 2006. Embryonic stem cell-derived microvesicles reprogram hematopoietic progenitors: evidence for horizontal transfer of mRNA and protein delivery. Leukemia 20(5):847-56.

93.

Raymond CR 2007. LTP forms 1, 2 and 3: different mechanisms for the "long" in long-term potentiation. Trends Neurosci 30(4):167-75.

94.

Rickman C. , Archer DA , Meunier FA , Craxton M. , Fukuda M. , Burgoyne RD , and others. 2004. Synaptotagmin interaction with the syntaxin/ SNAP-25 dimer is mediated by an evolutionarily conserved motif and is sensitive to inositol hexakisphosphate. J Biol Chem 279(13): 12574-9.

95.

Rinn JL , Kertesz M. , Wang JK , Squazzo SL , Xu X. , Brugmann SA , and others. 2007. Functional demarcation of active and silent chromatin domains in human HOX loci by noncoding RNAs. Cell 129(7):1311-23.

96.

Rogelj B. , Hartmann CE , Yeo CH , Hunt SP , Giese KP 2003. Contextual fear conditioning regulates the expression of brain-specific small nucleolar RNAs in hippocampus. Eur J Neurosci 18(11):3089-96.

97.

Schratt GM , Tuebing F. , Nigh EA , Kane CG , Sabatini ME , Kiebler M. , and others. 2006. A brain-specific microRNA regulates dendritic spine development. Nature 439(7074):283-9.

98.

Shamovsky I. , Nudler E. 2006. Gene control by large noncoding RNAs. Sci STKE 2006(355):pe40.

99.

Sleutels F. , Zwart R. , Barlow DP 2002. The non-coding Air RNA is required for silencing autosomal imprinted genes. Nature 415(6873):810-3.

100.

Spacek J. , Harris KM 2004. Trans-endocytosis via spinules in adult rat hippocampus . J Neurosci 24(17):4233-41.

101.

St Laurent G. 3rd , Wahlestedt C. 2007. Noncoding RNAs: couplers of analog and digital information in nervous system function? Trends Neurosci 30(12):612-21.

102.

Stark A. , Kheradpour P. , Parts L. , Brennecke J. , Hodges E. , Hannon GJ , and others. 2007. Systematic discovery and characterization of fly microRNAs using 12 Drosophila genomes. Genome Res 17(12):1865-79.

103.

Steidl S. , Rose JK , Rankin CH 2003. Stages of memory in the nematode Caenorhabditis elegans . Behav Cogn Neurosci Rev 2(1):3-14.

104.

Stough S. , Shobe JL , Carew TJ 2006. Intermediate-term processes in memory formation . Curr Opin Neurobiol 16(6):672-8.

105.

Struhl K. 2007. Transcriptional noise and the fidelity of initiation by RNA polymerase II. Nat Struct Mol Biol 14(2):103-5.

106.

Taft RJ , Pheasant M. , Mattick JS 2007. The relationship between non-protein-coding DNA and eukaryotic complexity. Bioessays 29(3):288-99.

107.

Valadi H. , Ekstrom K. , Bossios A. , Sjostrand M. , Lee JJ , Lotvall JO 2007. Exosome-mediated transfer of mRNAs and microRNAs is a novel mechanism of genetic exchange between cells. Nat Cell Biol 9(6):654-9.

108.

Valastro B. , Girard M. , Gagne J. , Martin F. , Parent AT , Baudry M. , and others. 2001. Inositol hexakisphosphate-mediated regulation of glutamate receptors in rat brain sections. Hippocampus 11(6):673-82.

109.

Vasudevan S. , Tong Y. , Steitz JA 2007. Switching from repression to activation: microRNAs can up-regulate translation. Science 318(5858):1931-4.

110.

Vessey JP , Vaccani A. , Xie Y. , Dahm R. , Karra D. , Kiebler MA , and others. 2006. Dendritic localization of the translational repressor Pumilio 2 and its contribution to dendritic stress granules. J Neurosci 26(24): 6496-508.

111.

Vo N. , Klein ME , Varlamova O. , Keller DM , Yamamoto T. , Goodman RH , and others. 2005. A cAMP-response element binding protein-induced microRNA regulates neuronal morphogenesis. Proc Natl Acad Sci U S A 102(45):16426-31.

112.

Wang H. , Iacoangeli A. , Lin D. , Williams K. , Denman RB , Hellen CU , and others. 2005. Dendritic BC1 RNA in translational control mechanisms. J Cell Biol 171(5):811-21.

113.

Weaver IC , Cervoni N. , Champagne FA , D' Alessio AC , Sharma S. , Seckl JR , and others. 2004. Epigenetic programming by maternal behavior . Nat Neurosci 7(8):847-54.

114.

Willingham AT , Orth AP , Batalov S. , Peters EC , Wen BG , Aza-Blanc P. , and others. 2005. A strategy for probing the function of noncoding RNAs finds a repressor of NFAT. Science 309(5740):1570-3.

115.

Winston WM , Molodowitch C. , Hunter CP 2002. Systemic RNAi in C. elegans requires the putative transmembrane protein SID-1. Science 295(5564):2456-9.

116.

Wolfrum C. , Shi S. , Jayaprakash KN , Jayaraman M. , Wang G. , Pandey RK , and others. 2007. Mechanisms and optimization of in vivo delivery of lipophilic siRNAs. Nat Biotechnol 25(10):1149-57.

117.

Yu W. , Gius D. , Onyango P. , Muldoon-Jacobs K. , Karp J. , Feinberg AP , and others. 2008. Epigenetic silencing of tumour suppressor gene p15 by its antisense RNA. Nature 451(7175):202-6.

118.

Zofall M. , Grewal SI 2006. RNAi-mediated heterochromatin assembly in fission yeast . Cold Spring Harb Symp Quant Biol 71:487-96.