Biogenesis and regulation of the let-7 miRNAs and their functional implications

Abstract

The let-7 miRNAwasone of thefirstmiRNAsdiscovered in the nematode, Caenorhabditis elegans, and its biological functions show a high level of evolutionary conservation from the nematode to the human. Unlike in C. elegans, higher animals have multiple isoforms of let-7 miRNAs; these isoforms share a consensus sequence called the ‘seed sequence’ and these isoforms are categorized into let-7 miRNA family. The expression of let-7 family is required for developmental timing and tumor suppressor function, but must be suppressed for the self-renewal of stem cells. Therefore, let-7 miRNA biogenesis must be carefully controlled. To generate a let-7 miRNA, a primary transcript is produced by RNA polymerase II and then subsequently processed by Drosha/DGCR8, TUTase, and Dicer. Because dysregulation of let-7 processing is deleterious, biogenesis of let-7 is tightly regulated by cellular factors, such as the RNA binding proteins, LIN28A/B and DIS3L2. In this review, we discuss the biological functions and biogenesis of let-7 miRNAs, focusing on the molecular mechanisms of regulation of let-7 biogenesis in vertebrates, such as the mouse and the human.

Key words： miRNA processing; miRNA biogenesis; let-7 family; TUTase; LIN28A/B

References

1 Abbott AL, Alvarez-Saavedra E, Miska EA, Lau NC, Bartel DP, Horvitz HR, Ambros V (2005) The let-7 MicroRNA family members mir-48, mir-84, and mir-241 function together to regulate developmental timing in Caenorhabditis elegans . Dev Cell 9:403–414

2 Ameres SL, Zamore PD (2013) Diversifying microRNA sequence and function . Nat Rev Mol Cell Biol 14:475–488

3 Azuma-Mukai A, Oguri H, Mituyama T, Qian ZR, Asai K, Siomi H, Siomi MC (2008) Characterization of endogenous human Argonautes and their miRNA partners in RNA silencing . Proc Natl Acad Sci USA 105:7964–7969

4 Bashirullah A, Pasquinelli AE, Kiger AA, Perrimon N, Ruvkun G, Thummel CS(2003) Coordinate regulationofsmall temporal RNAs at the onset of Drosophila metamorphosis . Dev Biol 259:1–8

5 Berezikov E, Chung WJ, Willis J, Cuppen E, Lai EC (2007) Mammalian mirtron genes . Mol Cell 28:328–336

6 Bernstein E, Caudy AA, Hammond SM, Hannon GJ (2001) Role for a bidentate ribonuclease in the initiation step of RNA interference . Nature 409:363–366

7 Bethke A, Fielenbach N, Wang Z, Mangelsdorf DJ, Antebi A(2009) Nuclear hormone receptor regulation of microRNAs controls developmental progression . Science 324:95–98

8 Bohnsack MT, Czaplinski K, Gorlich D (2004) Exportin 5 is a RanGTP-dependent dsRNA-binding protein that mediates nuclear export of pre-miRNAs . RNA 10:185–191

9 Boyerinas B, Park SM, Shomron N, Hedegaard MM, Vinther J, Andersen JS, Feig C, Xu J, Burge CB, Peter ME (2008) Identification of let-7-regulated oncofetal genes . Cancer Res 68:2587–2591

10 Boyerinas B, Park SM, Hau A, Murmann AE, Peter ME (2010) The role of let-7 in cell differentiation and cancer . Endocr Relat Cancer 17:F19–F36

11 Bracht J, Hunter S, Eachus R, Weeks P, Pasquinelli AE (2004) Trans-splicing and polyadenylation of let-7 microRNA primary transcripts . RNA 10:1586–1594

12 Brennecke J, Stark A, Russell RB, Cohen SM (2005) Principles of microRNA-target recognition . PLoS Biol 3:e85

13 Caygill EE, Johnston LA (2008)Temporal regulation of metamorphic processes in Drosophila by the let-7 and miR-125 heterochronic microRNAs . Curr Biol 18:943–950

14 Chang TC, Yu D, Lee YS, Wentzel EA, Arking DE, West KM, Dang CV, Thomas-Tikhonenko A, Mendell JT (2008) Widespread microRNA repression by Myc contributes to tumorigenesis . Nat Genet 40:43–50

15 Chang HM, Triboulet R, Thornton JE, Gregory RI (2013) A role for the Perlman syndrome exonuclease Dis3l2 in the Lin28-let-7 pathway . Nature 497:244–248

16 Cheloufi S, Dos Santos CO, Chong MM, Hannon GJ (2010)Adicerindependent miRNA biogenesis pathway that requires Ago catalysis . Nature 465:584–589

17 Chen PY, Manninga H, Slanchev K, Chien M, Russo JJ, Ju J, Sheridan R, John B, Marks DS, Gaidatzis D (2005) The developmental miRNA profiles of zebrafish as determined by small RNA cloning . Genes Dev 19:1288–1293

18 Chiu SC, Chung HY, Cho DY, Chan TM, Liu MC, Huang HM, Li TY, Lin JY, Chou PC, Fu RH (2014) Therapeutic potential of microRNA let-7: tumor suppression or impeding normal stemness . CellTransplant 23:459–469

19 Cifuentes D, Xue H, Taylor DW, Patnode H, Mishima Y, Cheloufi S, Ma E, Mane S, Hannon GJ, Lawson ND (2010) A novel miRNA processing pathway independent of Dicer requires Argonaute2 catalytic activity . Science 328:1694–1698

20 Copley MR, Babovic S, Benz C, Knapp DJ, Beer PA, Kent DG, Wohrer S, Treloar DQ, Day C, Rowe K (2013) The Lin28blet-7-Hmga2 axis determines the higher self-renewal potential of fetal haematopoietic stem cells . Nat Cell Biol 15:916–925

21 Dahiya N, Sherman-Baust CA, Wang TL, Davidson B, Shih Ie M, Zhang Y, Wood W 3rd, Becker KG, Morin PJ (2008) MicroRNA expression and identification of putative miRNA targets in ovarian cancer . PLoS One 3:e2436

22 Denli AM, Tops BB, Plasterk RH, Ketting RF, Hannon GJ (2004) Processing of primary microRNAs by the microprocessor complex . Nature 432:231–235

23 Desjardins A, Bouvette J, Legault P (2014) Stepwise assembly of multiple Lin28 proteins on the terminal loop of let-7 miRNA precursors . Nucleic Acids Res 42:4615–4628

24 Dueck A, Ziegler C, Eichner A, Berezikov E, Meister G (2012) microRNAs associated with the different human Argonaute proteins . Nucleic Acids Res 40:9850–9862

25 Emmrich S, Rasche M, Schoning J, Reimer C, Keihani S, Maroz A, Xie Y, Li Z, Schambach A, Reinhardt D (2014) miR-99a/ 100～125b tricistrons regulate hematopoietic stem and progenitor cell homeostasis by shifting the balance between TGFbeta and Wnt signaling . Genes Dev 28:858–874

26 Esquela-Kerscher A, Johnson SM, Bai L, Saito K, Partridge J, Reinert KL, Slack FJ (2005) Post-embryonic expression of C. elegans microRNAs belonging to the lin-4 and let-7 families in the hypodermis and the reproductive system . Dev Dyn 234:868–877

27 Eulalio A, Behm-Ansmant I, Schweizer D, Izaurralde E (2007) P-body formation is a consequence, not the cause, of RNA-mediated gene silencing . Mol Cell Biol 27:3970–3981

28 Eulalio A, Huntzinger E, Izaurralde E (2008) Getting to the root of miRNA-mediated gene silencing . Cell 132:9–14

29 Faehnle CR, Walleshauser J, Joshua-Tor L (2014) Mechanism of Dis3l2 substrate recognition in the Lin28-let-7 pathway . Nature 514:252–256

30 Filipowicz W, Bhattacharyya SN, Sonenberg N (2008) Mechanisms of post-transcriptional regulation by microRNAs: are the answers in sight ? Nat Rev Genet 9:102–114

31 Flynt AS, Greimann JC, Chung WJ, Lima CD, Lai EC (2010) MicroRNA biogenesis via splicing and exosome-mediated trimming in Drosophila . Mol Cell 38:900–907

32 Gerrits A, Walasek MA, Olthof S, Weersing E, Ritsema M, Zwart E, van Os R, Bystrykh LV, de Haan G ( 2012) Genetic screen identifies microRNA cluster 99b/let-7e/125a as a regulator of primitive hematopoietic cells . Blood 119: 377–387

33 Gregory RI, Yan KP, Amuthan G, Chendrimada T, Doratotaj B, Cooch N, Shiekhattar R (2004) The microprocessor complex mediates the genesis of microRNAs . Nature 432:235–240

34 Gregory RI, Chendrimada TP, Cooch N, Shiekhattar R (2005) Human RISC couples microRNA biogenesis and posttranscriptional gene silencing . Cell 123:631–640

35 Grimson A, Farh KK, Johnston WK, Garrett-Engele P, Lim LP, Bartel DP (2007) MicroRNA targeting specificity in mammals: determinants beyond seed pairing . Mol Cell 27:91–105

36 Grishok A, Pasquinelli AE, Conte D, Li N, Parrish S, Ha I, Baillie DL, Fire A, Ruvkun G, Mello CC (2001) Genes and mechanisms related to RNA interference regulate expression of the small temporal RNAs that control C. elegans developmental timing . Cell 106:23–34

37 Grosshans H, Johnson T, Reinert KL, Gerstein M, Slack FJ (2005) The temporal patterning microRNA let-7 regulates several transcription factors at the larval to adult transition in C. elegans . Dev Cell 8:321–330

38 Gunzburg MJ, Sivakumaran A, Pendini NR, Yoon JH, Gorospe M, Wilce MC, Wilce JA (2015) Cooperative interplay of let-7 mimic and HuR with MYC RNA . Cell Cycle.

39 Ha M, Kim VN (2014) Regulation of microRNA biogenesis . Nat Rev Mol Cell Biol 15:509–524

40 Hagan JP, Piskounova E, Gregory RI (2009) Lin28 recruits the TUTase Zcchc11 to inhibit let-7 maturation in mouse embryonic stem cells . Nat Struct Mol Biol 16:1021–1025

41 Hammell CM, Karp X, Ambros V(2009)Afeedback circuit involving let-7-family miRNAs and DAF-12 integrates environmental signals and developmental timing in Caenorhabditis elegans . Proc Natl Acad Sci USA 106:18668–18673

42 Hayes GD, Ruvkun G (2006) Misexpression of the Caenorhabditis elegans miRNA let-7 is sufficient to drive developmental programs . Cold Spring Harb Symp Quant Biol 71:21–27

43 Heo I, Joo C, Cho J, Ha M, Han J, Kim VN (2008) Lin28 mediates the terminal uridylation of let-7 precursor MicroRNA . Mol Cell 32:276–284

44 Heo I, Joo C, Kim YK, Ha M, Yoon MJ, Cho J, Yeom KH, Han J, Kim VN (2009) TUT4 in concert with Lin28 suppresses microRNA biogenesis through pre-microRNA uridylation . Cell 138:696–708

45 Heo I, Ha M, Lim J, Yoon MJ, Park JE, Kwon SC, Chang H, Kim VN (2012) Mono-uridylation of pre-microRNA as a key step in the biogenesis of group II let-7 microRNAs . Cell 151:521–532

46 Hertel J, Bartschat S, Wintsche A, Otto C, Stadler PF (2012) Evolution of the let-7 microRNA family . RNA Biol 9:231–241

47 Hibio N, Hino K, Shimizu E, Nagata Y, Ui-Tei K (2012) Stability of miRNA 5'terminal and seed regions is correlated with experimentally observed miRNA-mediated silencing efficacy . Sci Rep 2:996

48 Hutvagner G, McLachlan J, Pasquinelli AE, Balint E, Tuschl T, Zamore PD (2001) A cellular function for the RNA-interference enzyme Dicer in the maturation of the let-7 small temporal RNA . Science 293:834–838

49 Johnson SM, Grosshans H, Shingara J, Byrom M, Jarvis R, Cheng A, Labourier E, Reinert KL, Brown D, Slack FJ (2005) RAS is regulated by the let-7 microRNA family . Cell 120:635–647

50 Johnson CD, Esquela-Kerscher A, Stefani G, Byrom M, Kelnar K, Ovcharenko D, Wilson M, Wang X, Shelton J, Shingara J (2007) The let-7 microRNA represses cell proliferation pathways in human cells . Cancer Res 67:7713–7722

51 Ketting RF, Fischer SE, Bernstein E, Sijen T, Hannon GJ, Plasterk RH (2001) Dicer functions in RNA interference and in synthesis of small RNA involved in developmental timing in C. elegans . Genes Dev 15:2654–2659

52 Kim HH, Kuwano Y, Srikantan S, Lee EK, Martindale JL, Gorospe M (2009) HuR recruits let-7/RISC to repress c-Myc expression . Genes Dev 23:1743–1748

53 Kim SK, Lee H, Han K, Kim SC, Choi Y, Park SW, Bak G, Lee Y, Choi JK, Kim TK (2014) SET7/9 methylation of the pluripotency factor LIN28A is a nucleolar localization mechanism that blocks let-7 biogenesis in human ESCs . Cell Stem Cell 15:735–749

54 Knight SW, Bass BL (2001)Arole for the RNase III enzyme DCR-1 in RNA interference and germ line development in Caenorhabditis elegans . Science 293:2269–2271

55 Kumar MS, Erkeland SJ, Pester RE, Chen CY, Ebert MS, Sharp PA, Jacks T (2008) Suppression of non-small cell lung tumor development by the let-7 microRNA family . Proc Natl Acad Sci USA 105:3903–3908

56 Lagos-Quintana M, Rauhut R, Lendeckel W, Tuschl T (2001) Identification of novel genes coding for small expressed RNAs . Science 294:853–858

57 Lancman JJ, Caruccio NC, Harfe BD, Pasquinelli AE, Schageman JJ, Pertsemlidis A, Fallon JF (2005) Analysis of the regulation of lin-41 during chick and mouse limb development . Dev Dyn 234:948–960

58 Landgraf P, Rusu M, Sheridan R, Sewer A, Iovino N, Aravin A, Pfeffer S, Rice A, Kamphorst AO, Landthaler M (2007) A mammalian microRNA expression atlas based on small RNA library sequencing . Cell 129:1401–1414

59 Landthaler M, Yalcin A, Tuschl T (2004) The human DiGeorge syndrome critical region gene8and ItsD. melanogaster homolog are required for miRNA biogenesis . Curr Biol 14:2162–2167

60 Lau NC, Lim LP, Weinstein EG, Bartel DP (2001) An abundant class of tiny RNAs with probable regulatory roles in Caenorhabditis elegans . Science 294:858–862

61 Lee Y, Ahn C, Han J, Choi H, Kim J, Yim J, Lee J, Provost P, Radmark O, Kim S (2003) The nuclear RNase III Drosha initiates microRNA processing . Nature 425:415–419

62 Lee Y, Hur I, Park SY, Kim YK, Suh MR, Kim VN (2006)Theroleof PACT in the RNA silencing pathway . EMBOJ 25:522–532

63 Lee EJ, Baek M, Gusev Y, Brackett DJ, Nuovo GJ, Schmittgen TD (2008) Systematic evaluation of microRNA processing patterns in tissues, cell lines, and tumors . RNA 14:35–42

64 Lee HY, Zhou K, Smith AM, Noland CL, Doudna JA (2013a) Differential roles of human Dicer-binding proteins TRBP and PACT in small RNA processing . Nucleic Acids Res 41:6568–6576

65 Lee YT, de Vasconcellos JF, Yuan J, Byrnes C, Noh SJ, Meier ER, Kim KS, Rabel A, Kaushal M, Muljo SA (2013b) LIN28Bmediated expression of fetal hemoglobin and production of fetal-like erythrocytes from adult human erythroblasts ex vivo . Blood 122:1034–1041

66 Liu J, Carmell MA, Rivas FV, Marsden CG, Thomson JM, Song JJ, Hammond SM, Joshua-Tor L, Hannon GJ (2004) Argonaute2 is the catalytic engine of mammalian RNAi . Science 305:1437–1441

67 Liu J, Valencia-Sanchez MA, Hannon GJ, Parker R (2005) MicroRNA-dependent localization of targeted mRNAs to mammalian P-bodies . Nat Cell Biol 7:719–723

68 Liu S, Xia Q, Zhao P, Cheng T, Hong K, Xiang Z (2007) Characterization and expression patterns of let-7 microRNA in the silkworm(Bombyx mori) . BMC Dev Biol 7:88

69 Lund E, Guttinger S, Calado A, Dahlberg JE, Kutay U (2004) Nuclear export of microRNA precursors . Science 303:95–98

70 Ma WJ, Cheng S, Campbell C, Wright A, Furneaux H(1996) Cloning and characterization of HuR, a ubiquitously expressed Elav-like protein . J Biol Chem 271:8144–8151

71 Macrae IJ, Zhou K, Li F, Repic A, Brooks AN, Cande WZ, Adams PD, Doudna JA (2006) Structural basis for double-stranded RNA processing by Dicer . Science 311:195–198

72 MacRae IJ, Zhou K, Doudna JA (2007) Structural determinants of RNA recognition and cleavage by Dicer . Nat Struct Mol Biol 14:934–940

73 Malecki M, Viegas SC, Carneiro T, Golik P, Dressaire C, Ferreira MG, Arraiano CM (2013) The exoribonuclease Dis3L2 defines a novel eukaryotic RNA degradation pathway . EMBO J 32:1842–1854

74 Mansfield JH, Harfe BD, Nissen R, Obenauer J, Srineel J, Chaudhuri A, Farzan-Kashani R, Zuker M, Pasquinelli AE, Ruvkun G (2004) MicroRNA-responsive 'sensor' transgenes uncover Hox-like and other developmentally regulated patterns of vertebrate microRNA expression . Nat Genet 36: 1079–1083

75 Meister G, Landthaler M, Patkaniowska A, Dorsett Y, Teng G, Tuschl T (2004) Human Argonaute2 mediates RNA cleavage targeted by miRNAs and siRNAs . Mol Cell 15:185–197

76 Moss EG (2007) Heterochronic genes and the nature of developmental time . Curr Biol 17:R425–R434

77 Moss EG, Tang L(2003) Conservationofthe heterochronic regulator Lin-28, its developmental expression and microRNA complementary sites . Dev Biol 258:432–442

78 Nam Y, Chen C, Gregory RI, Chou JJ, Sliz P(2011) Molecular basis for interaction of let-7 microRNAs with Lin28 . Cell 147:1080–1091

79 Newman MA, Thomson JM, Hammond SM (2008) Lin-28 interaction with the Let-7 precursor loop mediates regulated microRNA processing . RNA 14:1539–1549

80 Nishino J, Kim I, Chada K, Morrison SJ (2008) Hmga2 promotes neural stem cell self-renewal in young but not old mice by reducing p16 Ink4a and p19 Arf expression . Cell 135:227–239

81 O'Hara AJ, Wang L, Dezube BJ, Harrington WJ Jr, Damania B, Dittmer DP (2009) Tumor suppressor microRNAs are underrepresented in primary effusion lymphoma and Kaposi sarcoma . Blood 113:5938–5941

82 Okamura K, Ishizuka A, Siomi H, Siomi MC (2004) Distinct roles for Argonaute proteins in small RNA-directed RNA cleavage pathways . Genes Dev 18:1655–1666

83 Okamura K, Hagen JW, Duan H, Tyler DM, Lai EC (2007) The mirtron pathway generates microRNA-class regulatory RNAs in Drosophila . Cell 130:89–100

84 Park JE, Heo I, Tian Y, Simanshu DK, Chang H, Jee D, Patel DJ, Kim VN (2011) Dicer recognizes the 5' end of RNA for efficient and accurate processing . Nature 475:201–205

85 Pasquinelli AE, Reinhart BJ, Slack F, Martindale MQ, Kuroda MI, Maller B, Hayward DC, Ball EE, Degnan B, Muller P (2000) Conservation of the sequence and temporal expression of let-7 heterochronic regulatory RNA . Nature 408:86–89

86 Piskounova E, Polytarchou C, Thornton JE, LaPierre RJ, Pothoulakis C, Hagan JP, Iliopoulos D, Gregory RI (2011) Lin28A and Lin28B inhibit let-7 microRNA biogenesis by distinct mechanisms . Cell 147:1066–1079

87 Reinhart BJ, Slack FJ, Basson M, Pasquinelli AE, Bettinger JC, Rougvie AE, Horvitz HR, Ruvkun G(2000) The 21-nucleotide let7 RNA regulates developmental timing in Caenorhabditis elegans . Nature 403:901–906

88 Roush S, Slack FJ (2008) The let-7 family of microRNAs . Trends Cell Biol 18:505–516

89 Ruby JG, Jan C, Player C, Axtell MJ, Lee W, Nusbaum C, Ge H, Bartel DP (2006) Large-scale sequencing reveals 21U-RNAs and additional microRNAs and endogenous siRNAs in C. elegans . Cell 127:1193–1207

90 Ruby JG, Jan CH, Bartel DP (2007) Intronic microRNA precursors that bypass Drosha processing . Nature 448:83–86

91 Rybak A, Fuchs H, Smirnova L, Brandt C, Pohl EE, Nitsch R, Wulczyn FG (2008)A feedback loop comprising lin-28 and let-7 controls pre-let-7 maturation during neural stem-cell commitment . Nat Cell Biol 10:987–993

92 Sampson VB, Rong NH, Han J, Yang Q, Aris V, Soteropoulos P, Petrelli NJ, Dunn SP, Krueger LJ (2007) MicroRNA let-7a down regulates MYC and reverts MYC-induced growth in Burkitt lymphoma cells . Cancer Res 67:9762–9770

93 Schulman BR, Esquela-Kerscher A, Slack FJ (2005) Reciprocal expression of lin-41 and the microRNAs let-7 and mir-125 during mouse embryogenesis . Dev Dyn 234:1046–1054

94 Schultz J, Lorenz P, Gross G, Ibrahim S, Kunz M (2008) MicroRNA let-7b targets important cell cycle molecules in malignant melanoma cells and interferes with anchorage-independent growth . Cell Res 18:549–557

95 Segalla S, Pivetti S, Todoerti K, Chudzik MA, Giuliani EC, Lazzaro F, Volta V, Lazarevic D, Musco G, Muzi-Falconi M (2015)The ribonuclease DIS3 promotes let-7 miRNA maturation by degrading the pluripotency factor LIN28B mRNA . Nucleic Acids Res 43:5182–5193

96 Sempere LF, Dubrovsky EB, Dubrovskaya VA, Berger EM, Ambros V (2002) The expression of the let-7 small regulatory RNA is controlled by ecdysone during metamorphosis in Drosophila melanogaster . Dev Biol 244:170–179

97 Sempere LF, Sokol NS, Dubrovsky EB, Berger EM, Ambros V (2003) Temporal regulation of microRNA expression in Drosophila melanogaster mediated by hormonal signals and broad-Complex gene activity . Dev Biol 259:9–18

98 Sempere LF, Freemantle S, Pitha-Rowe I, Moss E, Dmitrovsky E, Ambros V(2004) Expression profiling of mammalian microRNAs uncovers a subset of brain-expressed microRNAs with possible roles in murine and human neuronal differentiation . Genome Biol 5:R13

99 Sempere LF, Christensen M, Silahtaroglu A, Bak M, Heath CV, Schwartz G, Wells W, Kauppinen S, Cole CN (2007) Altered MicroRNA expression confined to specific epithelial cell subpopulations in breast cancer . Cancer Res 67:11612–11620

100 Shell S, Park SM, Radjabi AR, Schickel R, Kistner EO, Jewell DA, Feig C, Lengyel E, Peter ME (2007) Let-7 expression defines two differentiation stages of cancer . Proc Natl Acad Sci USA 104:11400–11405

101 Sokol NS, Xu P, Jan YN, Ambros V (2008) Drosophila let-7 microRNA is required for remodeling of the neuromusculature during metamorphosis . Genes Dev 22:1591–1596

102 Su H, Trombly MI, Chen J, Wang X(2009) Essentialand overlapping functions for mammalian Argonautes in microRNA silencing . Genes Dev 23:304–317

103 Suh MR, Lee Y, Kim JY, Kim SK, Moon SH, Lee JY, Cha KY, Chung HM, Yoon HS, Moon SY (2004) Human embryonic stem cells express a unique set of microRNAs . Dev Biol 270:488–498

104 Suzuki HI, Katsura A, Miyazono K (2015) A role of uridylation pathway for blockade of let-7 microRNA biogenesis by Lin28B . Cancer Sci.

105 Takamizawa J, Konishi H, Yanagisawa K, Tomida S, Osada H, Endoh H, Harano T, Yatabe Y, Nagino M, Nimura Y (2004) Reduced expression of the let-7 microRNAs in human lung cancers in association with shortened postoperative survival . Cancer Res 64:3753–3756

106 Thomson JM, Parker J, Perou CM, Hammond SM (2004)A custom microarray platform for analysis of microRNA gene expression . Nat Methods 1:47–53

107 Thomson JM, Newman M, Parker JS, Morin-Kensicki EM, Wright T, Hammond SM (2006) Extensive post-transcriptional regulation of microRNAs and its implications for cancer . Genes Dev 20:2202–2207

108 Thornton JE, Gregory RI (2012) How does Lin28 let-7 control development and disease ? Trends Cell Biol 22:474–482

109 Thornton JE, Chang HM, Piskounova E, Gregory RI (2012) Lin28mediated control of let-7 microRNA expression by alternative TUTases Zcchc11 (TUT4) and Zcchc6 (TUT7) . RNA 18:1875–1885

110 Ustianenko D, Hrossova D, Potesil D, Chalupnikova K, Hrazdilova K, Pachernik J, Cetkovska K, Uldrijan S, Zdrahal Z, Vanacova S (2013) Mammalian DIS3L2 exoribonuclease targets the uridylated precursors of let-7 miRNAs . RNA 19:1632–1638

111 Vermeulen A, Behlen L, Reynolds A, Wolfson A, Marshall WS, Karpilow J, Khvorova A (2005) The contributions of dsRNA structure to Dicer specificity and efficiency . RNA 11:674–682

112 Viswanathan SR, Daley GQ, Gregory RI (2008) Selective blockade of microRNA processing by Lin28 . Science 320:97–100

113 Wada T, Kikuchi J, Furukawa Y (2012) Histone deacetylase 1 enhances microRNA processing via deacetylation of DGCR8 . EMBO Rep 13:142–149

114 Wang Z, Lin S, Li JJ, Xu Z, Yao H, Zhu X, Xie D, Shen Z, Sze J, Li K (2011) MYC protein inhibits transcription of the microRNA cluster MC-let-7a-1～let-7d via noncanonical E-box . J Biol Chem 286:39703–39714

115 Wilbert ML, Huelga SC, Kapeli K, Stark TJ, Liang TY, Chen SX, Yan BY, Nathanson JL, Hutt KR, Lovci MT (2012) LIN28 binds messenger RNAs at GGAGA motifs and regulates splicing factor abundance . Mol Cell 48:195–206

116 Wulczyn FG, Smirnova L, Rybak A, Brandt C, Kwidzinski E, Ninnemann O, Strehle M, Seiler A, Schumacher S, Nitsch R (2007) Post-transcriptional regulation of the let-7 microRNA during neural cell specification . FASEBJ 21:415–426

117 Yang JS, Maurin T, Robine N, Rasmussen KD, Jeffrey KL, Chandwani R, Papapetrou EP, Sadelain M, O'Carroll D, Lai EC (2010) Conserved vertebrate mir-451 provides a platform for Dicer-independent, Ago2-mediated microRNA biogenesis . Proc Natl Acad Sci USA 107:15163–15168

118 Yi R, Qin Y, Macara IG, Cullen BR (2003) Exportin-5 mediates the nuclear export of pre-microRNAs and short hairpin RNAs . Genes Dev 17:3011–3016

119 Yoda M, Cifuentes D, Izumi N, Sakaguchi Y, Suzuki T, Giraldez AJ, Tomari Y (2013) Poly(A)-specific ribonuclease mediates 3'-end trimming of Argonaute2-cleaved precursor microRNAs . Cell Rep 5:715–726

120 Yu F, Yao H, Zhu P, Zhang X, Pan Q, Gong C, Huang Y, Hu X, Su F, Lieberman J (2007) let-7 regulates self renewal and tumorigenicity of breast cancer cells . Cell 131:1109–1123

121 Zhang H, Kolb FA, Brondani V, Billy E, Filipowicz W (2002) Human Dicer preferentially cleaves dsRNAs at their termini without a requirement forATP . EMBOJ 21:5875–5885

122 Zhang H, Kolb FA, Jaskiewicz L, Westhof E, Filipowicz W (2004) Single processing center models for human Dicer and bacterial RNase III . Cell 118:57–68