Intracellular Compartmentalization: A Key Determinant of MicroRNA Functions

Rohit      Nalavade; Mohini      Singh
Abstract

Being an integral part of the eukaryotic transcriptome, miRNAs are regarded as vital regulators of diverse developmental and physiological processes. Clearly, miRNA activity is kept in check by various regulatory mechanisms that control their biogenesis and decay pathways. With the increasing technical depth of RNA profiling technologies, novel insights have unravelled the spatial diversity exhibited by miRNAs inside a cell. Compartmentalization of miRNAs adds complexity to the regulatory circuits of miRNA expression, thereby providing superior control over the miRNA function. This review provides a bird’s eye view of miRNAs expressed in different subcellular locations, thus affecting the gene regulatory pathways therein. Occurrence of miRNAs in diverse intracellular locales also reveals various unconventional roles played by miRNAs in different cellular organelles and expands the scope of miRNA functions beyond their traditionally known repressive activities.
Graphical Abstract

[1]
Bartel DP. MicroRNAs: Target recognition and regulatory functions. Cell  2009; 136(2): 215-33.
 [http://dx.doi.org/10.1016/j.cell.2009.01.002] [PMID: 19167326]

[2]
Kozomara A, Birgaoanu M, Griffiths-Jones S. miRBase: From microRNA sequences to function. Nucleic Acids Res  2019; 47(D1): D155-62.
 [http://dx.doi.org/10.1093/nar/gky1141] [PMID: 30423142]

[3]
Chi SW, Zang JB, Mele A, Darnell RB. Argonaute HITS-CLIP decodes microRNA–mRNA interaction maps. Nature  2009; 460(7254): 479-86.
 [http://dx.doi.org/10.1038/nature08170] [PMID: 19536157]

[4]
Hafner M, Landthaler M, Burger L, et al. Transcriptome-wide identification of RNA-binding protein and microRNA target sites by PAR-CLIP. Cell  2010; 141(1): 129-41.
 [http://dx.doi.org/10.1016/j.cell.2010.03.009] [PMID: 20371350]

[5]
Hanna J, Hossain GS, Kocerha J. The potential for microRNA therapeutics and clinical research. Front Genet  2019; 10: 478.
 [http://dx.doi.org/10.3389/fgene.2019.00478] [PMID: 31156715]

[6]
Klein U, Lia M, Crespo M, et al. The DLEU2/miR-15a/16-1 cluster controls B cell proliferation and its deletion leads to chronic lymphocytic leukemia. Cancer Cell  2010; 17(1): 28-40.
 [http://dx.doi.org/10.1016/j.ccr.2009.11.019] [PMID: 20060366]

[7]
Calin GA, Cimmino A, Fabbri M, et al. MiR-15a and miR-16-1 cluster functions in human leukemia. Proc Natl Acad Sci  2008; 105(13): 5166-71.
 [http://dx.doi.org/10.1073/pnas.0800121105] [PMID: 18362358]

[8]
Bartel DP. Metazoan MicroRNAs. Cell  2018; 173(1): 20-51.
 [http://dx.doi.org/10.1016/j.cell.2018.03.006] [PMID: 29570994]

[9]
Lu J, Getz G, Miska EA, et al. MicroRNA expression profiles classify human cancers. Nature  2005; 435(7043): 834-8.
 [http://dx.doi.org/10.1038/nature03702] [PMID: 15944708]

[10]
Rüegger S, Großhans H. MicroRNA turnover: When, how, and why. Trends Biochem Sci  2012; 37(10): 436-46.
 [http://dx.doi.org/10.1016/j.tibs.2012.07.002] [PMID: 22921610]

[11]
Gebert LFR, MacRae IJ. Regulation of microRNA function in animals. Nat Rev Mol Cell Biol  2019; 20(1): 21-37.
 [http://dx.doi.org/10.1038/s41580-018-0045-7] [PMID: 30108335]

[12]
Chatterjee S, Fasler M, Büssing I, Großhans H. Target-mediated protection of endogenous microRNAs in C. elegans. Dev Cell  2011; 20(3): 388-96.
 [http://dx.doi.org/10.1016/j.devcel.2011.02.008] [PMID: 21397849]

[13]
Ghini F, Rubolino C, Climent M, Simeone I, Marzi MJ, Nicassio F. Endogenous transcripts control miRNA levels and activity in mammalian cells by target-directed miRNA degradation. Nat Commun  2018; 9(1): 3119.
 [http://dx.doi.org/10.1038/s41467-018-05182-9] [PMID: 30087332]

[14]
Kim YK, Heo I, Kim VN. Modifications of small RNAs and their associated proteins. Cell  2010; 143(5): 703-9.
 [http://dx.doi.org/10.1016/j.cell.2010.11.018] [PMID: 21111232]

[15]
Kai ZS, Pasquinelli AE. MicroRNA assassins: factors that regulate the disappearance of miRNAs. Nat Struct Mol Biol  2010; 17(1): 5-10.
 [http://dx.doi.org/10.1038/nsmb.1762] [PMID: 20051982]

[16]
Biemar F, Zinzen R, Ronshaugen M, Sementchenko V, Manak JR, Levine MS. Spatial regulation of microRNA gene expression in the Drosophila embryo. Proc Natl Acad Sci  2005; 102(44): 15907-11.
 [http://dx.doi.org/10.1073/pnas.0507817102] [PMID: 16249329]

[17]
Pasquinelli AE, Reinhart BJ, Slack F, et al. Conservation of the sequence and temporal expression of let-7 heterochronic regulatory RNA. Nature  2000; 408(6808): 86-9.
 [http://dx.doi.org/10.1038/35040556] [PMID: 11081512]

[18]
Rybak A, Fuchs H, Hadian K, et al. The let-7 target gene mouse lin-41 is a stem cell specific E3 ubiquitin ligase for the miRNA pathway protein Ago2. Nat Cell Biol  2009; 11(12): 1411-20.
 [http://dx.doi.org/10.1038/ncb1987] [PMID: 19898466]

[19]
Wang J, Czech B, Crunk A, et al. Deep small RNA sequencing from the nematode Ascaris reveals conservation, functional diversification, and novel developmental profiles. Genome Res  2011; 21(9): 1462-77.
 [http://dx.doi.org/10.1101/gr.121426.111] [PMID: 21685128]

[20]
Martinez NJ, Ow MC, Reece-Hoyes JS, Barrasa MI, Ambros VR, Walhout AJM. Genome-scale spatiotemporal analysis of Caenorhabditis elegans microRNA promoter activity. Genome Res  2008; 18(12): 2005-15.
 [http://dx.doi.org/10.1101/gr.083055.108] [PMID: 18981266]

[21]
Lee EJ, Baek M, Gusev Y, Brackett DJ, Nuovo GJ, Schmittgen TD. Systematic evaluation of microRNA processing patterns in tissues, cell lines, and tumors. RNA  2008; 14(1): 35-42.
 [http://dx.doi.org/10.1261/rna.804508] [PMID: 18025253]

[22]
Newman MA, Thomson JM, Hammond SM. Lin-28 interaction with the Let-7 precursor loop mediates regulated microRNA processing. RNA  2008; 14(8): 1539-49.
 [http://dx.doi.org/10.1261/rna.1155108] [PMID: 18566191]

[23]
Ninova M, Ronshaugen M, Griffiths-Jones S. Conserved temporal patterns of microRNA expression in Drosophila support a developmental hourglass model. Genome Biol Evol  2014; 6(9): 2459-67.
 [http://dx.doi.org/10.1093/gbe/evu183] [PMID: 25169982]

[24]
Landgraf P, Rusu M, Sheridan R, et al. A mammalian microRNA expression atlas based on small RNA library sequencing. Cell  2007; 129(7): 1401-14.
 [http://dx.doi.org/10.1016/j.cell.2007.04.040] [PMID: 17604727]

[25]
Hinton A, Hunter SE, Afrikanova I, et al. sRNA-seq analysis of human embryonic stem cells and definitive endoderm reveals differentially expressed microRNAs and novel IsomiRs with distinct targets. Stem Cells  2014; 32(9): 2360-72.
 [http://dx.doi.org/10.1002/stem.1739] [PMID: 24805944]

[26]
Lim LP, Lau NC, Garrett-Engele P, et al. Microarray analysis shows that some microRNAs downregulate large numbers of target mRNAs. Nature  2005; 433(7027): 769-73.
 [http://dx.doi.org/10.1038/nature03315] [PMID: 15685193]

[27]
Trabucchi M, Briata P, Garcia-Mayoral M, et al. The RNA-binding protein KSRP promotes the biogenesis of a subset of microRNAs. Nature  2009; 459(7249): 1010-4.
 [http://dx.doi.org/10.1038/nature08025] [PMID: 19458619]

[28]
Park JE, Heo I, Tian Y, et al. Dicer recognizes the 5′ end of RNA for efficient and accurate processing. Nature  2011; 475(7355): 201-5.
 [http://dx.doi.org/10.1038/nature10198] [PMID: 21753850]

[29]
Zeng Y, Cullen BR. RNA interference in human cells is restricted to the cytoplasm. RNA  2002; 8(7): 855-60.
 [http://dx.doi.org/10.1017/S1355838202020071] [PMID: 12166640]

[30]
Bernstein E, Caudy AA, Hammond SM, Hannon GJ. Role for a bidentate ribonuclease in the initiation step of RNA interference. Nature  2001; 409(6818): 363-6.
 [http://dx.doi.org/10.1038/35053110] [PMID: 11201747]

[31]
MacRae IJ, Zhou K, Li F, et al. Structural basis for double-stranded RNA processing by Dicer. Science  2006; 311(5758): 195-8.
 [http://dx.doi.org/10.1126/science.1121638]

[32]
Gregory RI, Chendrimada TP, Cooch N, Shiekhattar R. Human RISC couples microRNA biogenesis and posttranscriptional gene silencing. Cell  2005; 123(4): 631-40.
 [http://dx.doi.org/10.1016/j.cell.2005.10.022] [PMID: 16271387]

[33]
Matranga C, Tomari Y, Shin C, Bartel DP, Zamore PD. Passenger-strand cleavage facilitates assembly of siRNA into Ago2-containing RNAi enzyme complexes. Cell  2005; 123(4): 607-20.
 [http://dx.doi.org/10.1016/j.cell.2005.08.044] [PMID: 16271386]

[34]
Pillai RS, Bhattacharyya SN, Artus CG, et al. Molecular biology: Inhibition of translational initiation by let-7 microRNA in human cells. Science  2005; 309(5740): 1573-6.

[35]
Humphreys DT, Westman BJ, Martin DIK, Preiss T. MicroRNAs control translation initiation by inhibiting eukaryotic initiation factor 4E/cap and poly(A) tail function. Proc Natl Acad Sci  2005; 102(47): 16961-6.
 [http://dx.doi.org/10.1073/pnas.0506482102] [PMID: 16287976]

[36]
Liu J, Valencia-Sanchez MA, Hannon GJ, Parker R. MicroRNA-dependent localization of targeted mRNAs to mammalian P-bodies. Nat Cell Biol  2005; 7(7): 719-23.
 [http://dx.doi.org/10.1038/ncb1274] [PMID: 15937477]

[37]
Eulalio A, Behm-Ansmant I, Schweizer D, Izaurralde E. P-body formation is a consequence, not the cause, of RNA-mediated gene silencing. Mol Cell Biol  2007; 27(11): 3970-81.
 [http://dx.doi.org/10.1128/MCB.00128-07] [PMID: 17403906]

[38]
Chu C, Rana TM. Translation repression in human cells by microRNA-induced gene silencing requires RCK/p54. PLoS Biol  2006; 4(7): e210.
 [http://dx.doi.org/10.1371/journal.pbio.0040210] [PMID: 16756390]

[39]
Sheth U, Parker R. Decapping and decay of messenger RNA occur in cytoplasmic processing bodies. Science  2003; 300(5620): 805-8.
 [http://dx.doi.org/10.1126/science.1082320]

[40]
Bhattacharyya SN, Habermacher R, Martine U, Closs EI, Filipowicz W. Relief of microRNA-mediated translational repression in human cells subjected to stress. Cell  2006; 125(6): 1111-24.
 [http://dx.doi.org/10.1016/j.cell.2006.04.031] [PMID: 16777601]

[41]
Stalder L, Heusermann W, Sokol L, et al. The rough endoplasmatic reticulum is a central nucleation site of siRNA-mediated RNA silencing. EMBO J  2013; 32(8): 1115-27.
 [http://dx.doi.org/10.1038/emboj.2013.52] [PMID: 23511973]

[42]
Barman B, Bhattacharyya SN. mRNA targeting to endoplasmic reticulum precedes AGO protein interaction and MicroRNA (miRNA)-mediated translation repression in mammalian cells. J Biol Chem  2015; 290(41): 24650-6.
 [http://dx.doi.org/10.1074/jbc.C115.661868] [PMID: 26304123]

[43]
Upton JP, Wang L, Han D, et al. IRE1α cleaves select microRNAs during ER stress to derepress translation of proapoptotic Caspase-2. Science  2012; 338(6108): 818-22.
 [http://dx.doi.org/10.1126/science.1226191] [PMID: 23042294]

[44]
Wu PH, Isaji M, Carthew RW. Functionally diverse microRNA effector complexes are regulated by extracellular signaling. Mol Cell  2013; 52(1): 113-23.
 [http://dx.doi.org/10.1016/j.molcel.2013.08.023] [PMID: 24055343]

[45]
Su S-F, Chang Y-W, Andreu-Vieyra C, et al. miR-30d, miR-181a and miR-199a-5p cooperatively suppress the endoplasmic reticulum chaperone and signaling regulator GRP78 in cancer. Oncogene  2013; 32(39): 4694-701.
 [http://dx.doi.org/10.1038/onc.2012.483] [PMID: 23085757]

[46]
Dai B-H, Geng L, Wang Y, et al. microRNA-199a-5p protects hepatocytes from bile acid-induced sustained endoplasmic reticulum stress. Cell Death Dis  2013; 4(4): e604.
 [http://dx.doi.org/10.1038/cddis.2013.134] [PMID: 23598416]

[47]
Barrey E, Saint-Auret G, Bonnamy B, Damas D, Boyer O, Gidrol X. Pre-microRNA and mature microRNA in human mitochondria. PLoS One  2011; 6(5): e20220.
 [http://dx.doi.org/10.1371/journal.pone.0020220] [PMID: 21637849]

[48]
Wang G, Chen HW, Oktay Y, et al. PNPASE regulates RNA import into mitochondria. Cell  2010; 142(3): 456-67.
 [http://dx.doi.org/10.1016/j.cell.2010.06.035] [PMID: 20691904]

[49]
Wang WX, Visavadiya NP, Pandya JD, Nelson PT, Sullivan PG, Springer JE. Mitochondria-associated microRNAs in rat hippocampus following traumatic brain injury. Exp Neurol  2015; 265: 84-93.
 [http://dx.doi.org/10.1016/j.expneurol.2014.12.018] [PMID: 25562527]

[50]
Bandiera S, Rüberg S, Girard M, et al. Nuclear outsourcing of RNA interference components to human mitochondria. PLoS One  2011; 6(6): e20746.
 [http://dx.doi.org/10.1371/journal.pone.0020746] [PMID: 21695135]

[51]
Zhang X, Zuo X, Yang B, et al. MicroRNA directly enhances mitochondrial translation during muscle differentiation. Cell  2014; 158(3): 607-19.
 [http://dx.doi.org/10.1016/j.cell.2014.05.047] [PMID: 25083871]

[52]
Das S, Ferlito M, Kent OA, et al. Nuclear miRNA regulates the mitochondrial genome in the heart. Circ Res  2012; 110(12): 1596-603.
 [http://dx.doi.org/10.1161/CIRCRESAHA.112.267732] [PMID: 22518031]

[53]
Fan S, Tian T, Chen W, et al. Mitochondrial miRNA determines chemoresistance by reprogramming metabolism and regulating mitochondrial transcription. Cancer Res  2019; 79(6): 1069-84.
 [http://dx.doi.org/10.1158/0008-5472.CAN-18-2505] [PMID: 30659020]

[54]
Yan K, An T, Zhai M, et al. Mitochondrial miR-762 regulates apoptosis and myocardial infarction by impairing ND2. Cell Death Dis  2019; 10(7): 500.
 [http://dx.doi.org/10.1038/s41419-019-1734-7] [PMID: 31235686]

[55]
Sripada L, Tomar D, Prajapati P, Singh R, Singh AK, Singh RS. Systematic analysis of small RNAs associated with human mitochondria by deep sequencing: detailed analysis of mitochondrial associated miRNA. PLoS One  2012; 7(9): e44873.
 [http://dx.doi.org/10.1371/journal.pone.0044873]

[56]
Kren BT, Wong PYP, Sarver A, Zhang X, Zeng Y, Steer CJ. MicroRNAs identified in highly purified liver-derived mitochondria may play a role in apoptosis. RNA Biol  2009; 6(1): 65-72.
 [http://dx.doi.org/10.4161/rna.6.1.7534] [PMID: 19106625]

[57]
Das S, Bedja D, Campbell N, et al. miR-181c regulates the mitochondrial genome, bioenergetics, and propensity for heart failure in vivo. PLoS One  2014; 9(5): e96820.
 [http://dx.doi.org/10.1371/journal.pone.0096820] [PMID: 24810628]

[58]
Shepherd DL, Hathaway QA, Pinti MV, et al. Exploring the mitochondrial microRNA import pathway through Polynucleotide Phosphorylase (PNPase). J Mol Cell Cardiol  2017; 110: 15-25.
 [http://dx.doi.org/10.1016/j.yjmcc.2017.06.012] [PMID: 28709769]

[59]
Wang X, Song C, Zhou X, Han X, Li J, Wang Z, et al. Mitochondria associated MicroRNA expression profiling of heart failure. Biomed Res Int  2017; 2017: 4042509.
 [http://dx.doi.org/10.1155/2017/4042509]

[60]
Valadi H, Ekström K, Bossios A, Sjöstrand M, Lee JJ, Lötvall JO. Exosome-mediated transfer of mRNAs and microRNAs is a novel mechanism of genetic exchange between cells. Nat Cell Biol  2007; 9(6): 654-9.
 [http://dx.doi.org/10.1038/ncb1596] [PMID: 17486113]

[61]
Gibbings DJ, Ciaudo C, Erhardt M, Voinnet O. Multivesicular bodies associate with components of miRNA effector complexes and modulate miRNA activity. Nat Cell Biol  2009; 11(9): 1143-9.
 [http://dx.doi.org/10.1038/ncb1929] [PMID: 19684575]

[62]
Raiborg C, Stenmark H. The ESCRT machinery in endosomal sorting of ubiquitylated membrane proteins. Nature  2009; 458(7237): 445-52.
 [http://dx.doi.org/10.1038/nature07961] [PMID: 19325624]

[63]
Vasquez-Rifo A, Bossé GD, Rondeau EL, Jannot G, Dallaire A, Simard MJ. A new role for the GARP complex in microRNA-mediated gene regulation. PLoS Genet  2013; 9(11): e1003961.
 [http://dx.doi.org/10.1371/journal.pgen.1003961] [PMID: 24244204]

[64]
Kim YJ, Maizel A, Chen X. Traffic into silence: Endomembranes and post-transcriptional RNA silencing. EMBO J  2014; 33(9): 968-80.
 [http://dx.doi.org/10.1002/embj.201387262] [PMID: 24668229]

[65]
Bose M, Barman B, Goswami A, Bhattacharyya SN. Spatiotemporal uncoupling of MicroRNA-mediated translational repression and target RNA degradation controls MicroRNP recycling in mammalian cells. Mol Cell Biol  2017; 37(4): e00464-16.
 [http://dx.doi.org/10.1128/MCB.00464-16] [PMID: 27895152]

[66]
Lee YS, Pressman S, Andress AP, et al. Silencing by small RNAs is linked to endosomal trafficking. Nat Cell Biol  2009; 11(9): 1150-6.
 [http://dx.doi.org/10.1038/ncb1930] [PMID: 19684574]

[67]
Hu P, Wang K, Zhou D, et al. GOLPH3 regulates exosome miRNA secretion in glioma cells. J Mol Neurosci  2020; 70(8): 1257-66.
 [http://dx.doi.org/10.1007/s12031-020-01535-6] [PMID: 32227282]

[68]
Li H, Meng F, Ma J, et al. Insulin receptor substrate-1 and Golgi phosphoprotein 3 are downstream targets of miR-126 in esophageal squamous cell carcinoma. Oncol Rep  2014; 32(3): 1225-33.
 [http://dx.doi.org/10.3892/or.2014.3327] [PMID: 25017784]

[69]
Liu Y, Sun Y, Zhao A. MicroRNA-134 suppresses cell proliferation in gastric cancer cells via targeting of GOLPH3. Oncol Rep  2017; 37(4): 2441-8.
 [http://dx.doi.org/10.3892/or.2017.5488] [PMID: 28260021]

[70]
Zhang W, Chen X, Jia J. MiR-3150b-3p inhibits the progression of colorectal cancer cells via targeting GOLPH3. J Investig Med  2020; 68(2): 425-9.
 [http://dx.doi.org/10.1136/jim-2019-001124] [PMID: 31678970]

[71]
Núñez-Olvera SI, Chávez-Munguía B, del Rocío Terrones-Gurrola MC, et al. A novel protective role for microRNA-3135b in Golgi apparatus fragmentation induced by chemotherapy via GOLPH3/AKT1/mTOR axis in colorectal cancer cells. Sci Rep  2020; 10(1): 10555.
 [http://dx.doi.org/10.1038/s41598-020-67550-0] [PMID: 32601379]

[72]
Gagnon KT, Li L, Chu Y, Janowski BA, Corey DR. RNAi factors are present and active in human cell nuclei. Cell Rep  2014; 6(1): 211-21.
 [http://dx.doi.org/10.1016/j.celrep.2013.12.013] [PMID: 24388755]

[73]
Schraivogel D, Schindler SG, Danner J, et al. Importin-β facilitates nuclear import of human GW proteins and balances cytoplasmic gene silencing protein levels. Nucleic Acids Res  2015; 43(15): 7447-61.
 [http://dx.doi.org/10.1093/nar/gkv705] [PMID: 26170235]

[74]
Sarshad AA, Juan AH, Muler AIC, et al. Argonaute-miRNA complexes silence target mrnas in the nucleus of mammalian stem cells. Mol Cell  2018; 71(6): 1040-1050.e8.
 [http://dx.doi.org/10.1016/j.molcel.2018.07.020] [PMID: 30146314]

[75]
Nishi K, Nishi A, Nagasawa T, Ui-Tei K. Human TNRC6A is an argonaute-navigator protein for microRNA-mediated gene silencing in the nucleus. RNA  2013; 19(1): 17-35.
 [http://dx.doi.org/10.1261/rna.034769.112] [PMID: 23150874]

[76]
Weinmann L, Höck J, Ivacevic T, et al. Importin 8 is a gene silencing factor that targets argonaute proteins to distinct mRNAs. Cell  2009; 136(3): 496-507.
 [http://dx.doi.org/10.1016/j.cell.2008.12.023] [PMID: 19167051]

[77]
Meister G, Landthaler M, Patkaniowska A, Dorsett Y, Teng G, Tuschl T. Human Argonaute2 mediates RNA cleavage targeted by miRNAs and siRNAs. Mol Cell  2004; 15(2): 185-97.
 [http://dx.doi.org/10.1016/j.molcel.2004.07.007] [PMID: 15260970]

[78]
Hwang HW, Wentzel EA, Mendell JT. A hexanucleotide element directs microRNA nuclear import. Science  2007; 315(5808): 97-100.
 [http://dx.doi.org/10.1126/science.1136235]

[79]
Park CW, Zeng Y, Zhang X, Subramanian S, Steer CJ. Mature microRNAs identified in highly purified nuclei from HCT116 colon cancer cells. RNA Biol  2010; 7(5): 606-14.
 [http://dx.doi.org/10.4161/rna.7.5.13215] [PMID: 20864815]

[80]
Liao JY, Ma LM, Guo YH, et al. Deep sequencing of human nuclear and cytoplasmic small RNAs reveals an unexpectedly complex subcellular distribution of miRNAs and tRNA 3′ trailers. PLoS One  2010; 5(5): e10563.
 [http://dx.doi.org/10.1371/journal.pone.0010563] [PMID: 20498841]

[81]
Chatterjee S, Großhans H. Active turnover modulates mature microRNA activity in Caenorhabditis elegans. Nature  2009; 461(7263): 546-9.
 [http://dx.doi.org/10.1038/nature08349] [PMID: 19734881]

[82]
Turunen TA, Roberts TC, Laitinen P, et al. Changes in nuclear and cytoplasmic microRNA distribution in response to hypoxic stress. Sci Rep  2019; 9(1): 10332.
 [http://dx.doi.org/10.1038/s41598-019-46841-1] [PMID: 31316122]

[83]
Zaratiegui M, Castel SE, Irvine DV, et al. RNAi promotes heterochromatic silencing through replication-coupled release of RNA Pol II. Nature  2011; 479(7371): 135-8.
 [http://dx.doi.org/10.1038/nature10501] [PMID: 22002604]

[84]
Ameyar-Zazoua M, Rachez C, Souidi M, et al. Argonaute proteins couple chromatin silencing to alternative splicing. Nat Struct Mol Biol  2012; 19(10): 998-1004.
 [http://dx.doi.org/10.1038/nsmb.2373] [PMID: 22961379]

[85]
Leucci E, Patella F, Waage J, et al. microRNA-9 targets the long non-coding RNA MALAT1 for degradation in the nucleus. Sci Rep  2013; 3(1): 2535.
 [http://dx.doi.org/10.1038/srep02535] [PMID: 23985560]

[86]
Fasanaro P, Greco S, Lorenzi M, et al. An integrated approach for experimental target identification of hypoxia-induced miR-210. J Biol Chem  2009; 284(50): 35134-43.
 [http://dx.doi.org/10.1074/jbc.M109.052779] [PMID: 19826008]

[87]
Hansen TB, Wiklund ED, Bramsen JB, et al. miRNA-dependent gene silencing involving Ago2-mediated cleavage of a circular antisense RNA. EMBO J  2011; 30(21): 4414-22.
 [http://dx.doi.org/10.1038/emboj.2011.359] [PMID: 21964070]

[88]
Tang R, Li L, Zhu D, et al. Mouse miRNA-709 directly regulates miRNA-15a/16-1 biogenesis at the posttranscriptional level in the nucleus: evidence for a microRNA hierarchy system. Cell Res  2012; 22(3): 504-15.
 [http://dx.doi.org/10.1038/cr.2011.137] [PMID: 21862971]

[89]
Zisoulis DG, Kai ZS, Chang RK, Pasquinelli AE. Autoregulation of microRNA biogenesis by let-7 and Argonaute. Nature  2012; 486(7404): 541-4.
 [http://dx.doi.org/10.1038/nature11134] [PMID: 22722835]

[90]
Hicks JA, Li L, Matsui M, et al. Human GW182 paralogs are the central organizers for RNA-mediated control of transcription. Cell Rep  2017; 20(7): 1543-52.
 [http://dx.doi.org/10.1016/j.celrep.2017.07.058] [PMID: 28813667]

[91]
Verdel A, Jia S, Gerber S, Sugiyama T, Gygi S, Grewal SI MD. RNAi-mediated targeting of heterochromatin by the RITS complex. Science  2004; 303(5658): 672-6.
 [http://dx.doi.org/10.1126/science.1093686]

[92]
Abernathy DG, Kim WK, McCoy MJ, et al. MicroRNAs induce a permissive chromatin environment that enables neuronal subtype-specific reprogramming of adult human fibroblasts. Cell Stem Cell  2017; 21(3): 332-348.e9.
 [http://dx.doi.org/10.1016/j.stem.2017.08.002] [PMID: 28886366]

[93]
Krivdova G, Erwin SE, Voisin V, et al. Microrna-130a regulates hematopoietic stem cell self-renewal by repressing chromatin modifiers and shaping the accessible chromatin landscape. Blood  2018; 132(S1): 3824-4.
 [http://dx.doi.org/10.1182/blood-2018-99-116866]

[94]
Ritland Politz JC, Zhang F, Pederson T. MicroRNA-206 colocalizes with ribosome-rich regions in both the nucleolus and cytoplasm of rat myogenic cells. Proc Natl Acad Sci  2006; 103(50): 18957-62.
 [http://dx.doi.org/10.1073/pnas.0609466103] [PMID: 17135348]

[95]
Ritland Politz JC, Hogan EM, Pederson T. MicroRNAs with a nucleolar location. RNA  2009; 15(9): 1705-15.
 [http://dx.doi.org/10.1261/rna.1470409] [PMID: 19628621]

[96]
Li ZF, Liang YM, Lau PN, et al. Dynamic localisation of mature microRNAs in Human nucleoli is influenced by exogenous genetic materials. PLoS One  2013; 8(8): e70869.
 [http://dx.doi.org/10.1371/journal.pone.0070869] [PMID: 23940654]

[97]
Bai B, Liu H, Laiho M. Small RNA expression and deep sequencing analyses of the nucleolus reveal the presence of nucleolus-associated microRNAs. FEBS Open Biol  2014; 4(1): 441-9.
 [http://dx.doi.org/10.1016/j.fob.2014.04.010] [PMID: 24918059]

[98]
Atwood BL, Woolnough JL, Lefevre GM, Saint Just Ribeiro M, Felsenfeld G, Giles KE. Human argonaute 2 is tethered to ribosomal RNA through MicroRNA interactions. J Biol Chem  2016; 291(34): 17919-28.
 [http://dx.doi.org/10.1074/jbc.M116.725051] [PMID: 27288410]

[99]
Pisani G, Baron B. Nuclear paraspeckles function in mediating gene regulatory and apoptotic pathways. Noncoding RNA Res  2019; 4(4): 128-34.
 [http://dx.doi.org/10.1016/j.ncrna.2019.11.002] [PMID: 32072080]

[100]
Jiang L, Shao C, Wu QJ, et al. NEAT1 scaffolds RNA-binding proteins and the Microprocessor to globally enhance pri-miRNA processing. Nat Struct Mol Biol  2017; 24(10): 816-24.
 [http://dx.doi.org/10.1038/nsmb.3455] [PMID: 28846091]

[101]
West JA, Davis CP, Sunwoo H, et al. The long noncoding RNAs NEAT1 and MALAT1 bind active chromatin sites. Mol Cell  2014; 55(5): 791-802.
 [http://dx.doi.org/10.1016/j.molcel.2014.07.012] [PMID: 25155612]

[102]
Nakagawa S, Naganuma T, Shioi G, Hirose T. Paraspeckles are subpopulation-specific nuclear bodies that are not essential in mice. J Cell Biol  2011; 193(1): 31-9.
 [http://dx.doi.org/10.1083/jcb.201011110] [PMID: 21444682]

[103]
Yan H, Wang Z, Sun Y, Hu L, Bu P. Cytoplasmic NEAT1 suppresses AML stem cell self‐renewal and leukemogenesis through inactivation of Wnt signaling. Adv Sci  2021; 8(22): 2100914.
 [http://dx.doi.org/10.1002/advs.202100914] [PMID: 34609794]

[104]
Liang J, Liu C, Xu D, Xie K, Li A. LncRNA NEAT1 facilitates glioma progression via stabilizing PGK1. J Transl Med  2022; 20(1): 80.
 [http://dx.doi.org/10.1186/s12967-022-03273-2] [PMID: 35123484]

[105]
Turchinovich A, Samatov TR, Tonevitsky AGBB, Burwinkel B. Circulating miRNAs: cell-cell communication function? Front Genet  2013; 4(119): 119.
 [PMID: 23825476]

[106]
Ono M, Kosaka N, Tominaga N, et al. Exosomes from bone marrow mesenchymal stem cells contain a microRNA that promotes dormancy in metastatic breast cancer cells. Sci Signal  2014; 7(332): ra63.
 [http://dx.doi.org/10.1126/scisignal.2005231] [PMID: 24985346]

[107]
Mori MA, Ludwig RG, Garcia-Martin R, Brandão BB, Kahn CR. Extracellular miRNAs: From Biomarkers to Mediators of Physiology and Disease. Cell Metab  2019; 30(4): 656-73.
 [http://dx.doi.org/10.1016/j.cmet.2019.07.011] [PMID: 31447320]

[108]
Thomou T, Mori MA, Dreyfuss JM, et al. Adipose-derived circulating miRNAs regulate gene expression in other tissues. Nature  2017; 542(7642): 450-5.
 [http://dx.doi.org/10.1038/nature21365] [PMID: 28199304]

[109]
Castaño C, Kalko S, Novials A, Párrizas M. Obesity-associated exosomal miRNAs modulate glucose and lipid metabolism in mice. Proc Natl Acad Sci  2018; 115(48): 12158-63.
 [http://dx.doi.org/10.1073/pnas.1808855115] [PMID: 30429322]

[110]
Wang R, Hong J, Cao Y, et al. Elevated circulating microRNA-122 is associated with obesity and insulin resistance in young adults. Eur J Endocrinol  2015; 172(3): 291-300.
 [http://dx.doi.org/10.1530/EJE-14-0867] [PMID: 25515554]

[111]
Willeit P, Skroblin P, Moschen AR, et al. Circulating MicroRNA-122 is associated with the risk of new-onset metabolic syndrome and type 2 diabetes. Diabetes  2017; 66(2): 347-57.
 [http://dx.doi.org/10.2337/db16-0731] [PMID: 27899485]

[112]
Vickers KC, Palmisano BT, Shoucri BM, Shamburek RD, Remaley AT. MicroRNAs are transported in plasma and delivered to recipient cells by high-density lipoproteins. Nat Cell Biol  2011; 13(4): 423-33.
 [http://dx.doi.org/10.1038/ncb2210] [PMID: 21423178]

[113]
Zhang A, Li D, Liu Y, Li J, Zhang Y, Zhang CY. Islet β cell: An endocrine cell secreting miRNAs. Biochem Biophys Res Commun  2018; 495(2): 1648-54.
 [http://dx.doi.org/10.1016/j.bbrc.2017.12.028] [PMID: 29223394]

[114]
Lee HK, Finniss S, Cazacu S, Xiang C, Brodie C. Mesenchymal stem cells deliver exogenous miRNAs to neural cells and induce their differentiation and glutamate transporter expression. Stem Cells Dev  2014; 23(23): 2851-61.
 [http://dx.doi.org/10.1089/scd.2014.0146] [PMID: 25036385]

[115]
Manca S, Upadhyaya B, Mutai E, et al. Milk exosomes are bioavailable and distinct microRNA cargos have unique tissue distribution patterns. Sci Rep  2018; 8(1): 11321.
 [http://dx.doi.org/10.1038/s41598-018-29780-1] [PMID: 30054561]

[116]
Kosaka N, Izumi H, Sekine K, Ochiya T. microRNA as a new immune-regulatory agent in breast milk. Silence  2010; 1(1): 7.
 [http://dx.doi.org/10.1186/1758-907X-1-7] [PMID: 20226005]

[117]
Tsukamoto M, Iinuma H, Yagi T, Matsuda K, Hashiguchi Y. Circulating exosomal MicroRNA-21 as a biomarker in each tumor stage of colorectal cancer. Oncology  2017; 92(6): 360-70.
 [http://dx.doi.org/10.1159/000463387] [PMID: 28376502]

[118]
Wang H, Peng R, Wang J, Qin Z, Xue L. Circulating microRNAs as potential cancer biomarkers: the advantage and disadvantage. Clin Epigenet  2018; 10(1): 59.
 [http://dx.doi.org/10.1186/s13148-018-0492-1] [PMID: 29713393]

[119]
Arroyo JD, Chevillet JR, Kroh EM, et al. Argonaute2 complexes carry a population of circulating microRNAs independent of vesicles in human plasma. Proc Natl Acad Sci  2011; 108(12): 5003-8.
 [http://dx.doi.org/10.1073/pnas.1019055108] [PMID: 21383194]

[120]
Wang K, Zhang S, Weber J, Baxter D, Galas DJ. Export of microRNAs and microRNA-protective protein by mammalian cells. Nucleic Acids Res  2010; 38(20): 7248-59.
 [http://dx.doi.org/10.1093/nar/gkq601] [PMID: 20615901]

[121]
Shimizu C, Kim J, Stepanowsky P, et al. Differential expression of miR-145 in children with Kawasaki disease. PLoS One  2013; 8(3): e58159.
 [http://dx.doi.org/10.1371/journal.pone.0058159] [PMID: 23483985]

[122]
Tsai YW, Sung HH, Li JC, et al. Glia-derived exosomal miR-274 targets Sprouty in trachea and synaptic boutons to modulate growth and responses to hypoxia. Proc Natl Acad Sci  2019; 116(49): 24651-61.
 [http://dx.doi.org/10.1073/pnas.1902537116] [PMID: 31666321]

[123]
Lawrie CH, Gal S, Dunlop HM, et al. Detection of elevated levels of tumour-associated microRNAs in serum of patients with diffuse large B-cell lymphoma. Br J Haematol  2008; 141(5): 672-5.
 [http://dx.doi.org/10.1111/j.1365-2141.2008.07077.x] [PMID: 18318758]

[124]
Liu Q, Yu Z, Yuan S, et al. Circulating exosomal microRNAs as prognostic biomarkers for non-small-cell lung cancer. Oncotarget  2017; 8(8): 13048-58.
 [http://dx.doi.org/10.18632/oncotarget.14369] [PMID: 28055956]

[125]
Rashad NM, Ateya MAM, Saraya YS, et al. Association of miRNA − 320 expression level and its target gene endothelin-1 with the susceptibility and clinical features of polycystic ovary syndrome. J Ovarian Res  2019; 12(1): 39.
 [http://dx.doi.org/10.1186/s13048-019-0513-5]

[126]
Machida T, Tomofuji T, Maruyama T, et al. miR-1246 and miR-4644 in salivary exosome as potential biomarkers for pancreatobiliary tract cancer. Oncol Rep  2016; 36(4): 2375-81.
 [http://dx.doi.org/10.3892/or.2016.5021] [PMID: 27573701]

[127]
Rabinowits G, Gerçel-Taylor C, Day JM, Taylor DD, Kloecker GH. Exosomal microRNA: A diagnostic marker for lung cancer. Clin Lung Cancer  2009; 10(1): 42-6.
 [http://dx.doi.org/10.3816/CLC.2009.n.006] [PMID: 19289371]

[128]
Taylor DD, Gercel-Taylor C. MicroRNA signatures of tumor-derived exosomes as diagnostic biomarkers of ovarian cancer. Gynecol Oncol  2008; 110(1): 13-21.
 [http://dx.doi.org/10.1016/j.ygyno.2008.04.033] [PMID: 18589210]

[129]
Yang TT, Liu CG, Gao SC, Zhang Y, Wang PC. The serum exosome derived MicroRNA-135a, -193b, and -384 were potential Alzheimer’s disease biomarkers. Biomed Environ Sci  2018; 31(2): 87-96.
 [PMID: 29606187]

[130]
Gui Y, Liu H, Zhang L, Lv W, Hu X. Altered microRNA profiles in cerebrospinal fluid exosome in Parkinson disease and Alzheimer disease. Oncotarget  2015; 6(35): 37043-53.
 [http://dx.doi.org/10.18632/oncotarget.6158] [PMID: 26497684]

[131]
Wang GK, Zhu JQ, Zhang JT, et al. Circulating microRNA: A novel potential biomarker for early diagnosis of acute myocardial infarction in humans. Eur Heart J  2010; 31(6): 659-66.
 [http://dx.doi.org/10.1093/eurheartj/ehq013] [PMID: 20159880]

[132]
Eichelser C, Stückrath I, Müller V, et al. Increased serum levels of circulating exosomal microRNA-373 in receptor-negative breast cancer patients. Oncotarget  2014; 5(20): 9650-63.
 [http://dx.doi.org/10.18632/oncotarget.2520] [PMID: 25333260]

[133]
Sueta A, Yamamoto Y, Iwase H. The role of exosomal microRNAs; focus on clinical applications in breast cancer. Cancer Drug Resist  2019; 2(3): 847-61.
 [http://dx.doi.org/10.20517/cdr.2019.17] [PMID: 35582569]

[134]
Herwijnen MJC, Driedonks TAP, Snoek BL, et al. Abundantly present miRNAs in milk-derived extracellular vesicles are conserved between mammals. Front Nutr  2018; 5: 81.
 [http://dx.doi.org/10.3389/fnut.2018.00081] [PMID: 30280098]

[135]
Vizitiu AC, Stambouli D, Pavel AG, et al. Mature miR-99a upregulation in the amniotic fluid samples from female fetus down syndrome pregnancies: A pilot study. MedM  2019; 55(11)
 [http://dx.doi.org/10.3390/medicina55110728]

[136]
Hicks SD, Carpenter RL, Wagner KE, et al. Saliva MicroRNA differentiates children with autism from peers with typical and atypical development. J Am Acad Child Adolesc Psychiatry  2020; 59(2): 296-308.
 [http://dx.doi.org/10.1016/j.jaac.2019.03.017] [PMID: 30926572]

[137]
Wiegand C, Heusser P, Klinger C, et al. Stress-associated changes in salivary microRNAs can be detected in response to the Trier Social Stress Test: An exploratory study. Sci Rep  2018; 8(1): 7112.
 [http://dx.doi.org/10.1038/s41598-018-25554-x] [PMID: 29740073]

[138]
Muñoz-San Martín M, Reverter G, Robles-Cedeño R, et al. Analysis of miRNA signatures in CSF identifies upregulation of miR-21 and miR-146a/b in patients with multiple sclerosis and active lesions. J Neuroinflammation  2019; 16(1): 220.
 [http://dx.doi.org/10.1186/s12974-019-1590-5] [PMID: 31727077]

[139]
Kopkova A, Sana J, Fadrus P, Slaby O. Cerebrospinal fluid microRNAs as diagnostic biomarkers in brain tumors. Clinical Chemistry and Laboratory Medicine (CCLM)  2018; 56(6): 869-79.
 [http://dx.doi.org/10.1515/cclm-2017-0958] [PMID: 29451858]

[140]
Zardo G, Ciolfi A, vian L. Polycombs and microRNA-223 regulate human granulopoiesis by transcriptional control of target gene expression. (Blood (2012) 119, 17, (4034-4046)). Blood  2014; 123(8): 1279.
 [http://dx.doi.org/10.1182/blood-2014-01-548255]

[141]
Wang D, Sun X, Wei Y, et al. Nuclear miR-122 directly regulates the biogenesis of cell survival oncomiR miR-21 at the posttranscriptional level. Nucleic Acids Res  2018; 46(4): 2012-29.
 [http://dx.doi.org/10.1093/nar/gkx1254] [PMID: 29253196]

[142]
Zhang WL, Zhang JH. miR-181c promotes proliferation via suppressing PTEN expression in inflammatory breast cancer. Int J Oncol  2015; 46(5): 2011-20.
 [http://dx.doi.org/10.3892/ijo.2015.2896] [PMID: 25695913]

[143]
Ristori E, Lopez-Ramirez MA, Narayanan A, et al. A Dicer-miR-107 interaction regulates biogenesis of specific miRNAs crucial for neurogenesis. Dev Cell  2015; 32(5): 546-60.
 [http://dx.doi.org/10.1016/j.devcel.2014.12.013] [PMID: 25662174]

[144]
Bonev B, Pisco A, Papalopulu N. MicroRNA-9 reveals regional diversity of neural progenitors along the anterior-posterior axis. Dev Cell  2011; 20(1): 19-32.
 [http://dx.doi.org/10.1016/j.devcel.2010.11.018] [PMID: 21238922]

[145]
Ryan DG, Oliveira-Fernandes M, Lavker RM. MicroRNAs of the mammalian eye display distinct and overlapping tissue specificity. Mol Vis  2006; 12: 1175-84.
 [PMID: 17102797]

[146]
Yu J, Ryan DG, Getsios S, Oliveira-Fernandes M, Fatima A, Lavker RM. MicroRNA-184 antagonizes microRNA-205 to maintain SHIP2 levels in epithelia. Proc Natl Acad Sci  2008; 105(49): 19300-5.
 [http://dx.doi.org/10.1073/pnas.0803992105] [PMID: 19033458]

[147]
Pase L, Layton JE, Kloosterman WP, Carradice D, Waterhouse PM, Lieschke GJ. miR-451 regulates zebrafish erythroid maturation in vivo via its target gata2. Blood  2009; 113(8): 1794-804.
 [http://dx.doi.org/10.1182/blood-2008-05-155812] [PMID: 18849488]

[148]
Yu D, dos Santos CO, Zhao G, et al. miR-451 protects against erythroid oxidant stress by repressing 14-3-3ζ. Genes Dev  2010; 24(15): 1620-33.
 [http://dx.doi.org/10.1101/gad.1942110] [PMID: 20679398]

[149]
Tsuchiya S, Oku M, Imanaka Y, et al. MicroRNA-338-3p and microRNA-451 contribute to the formation of basolateral polarity in epithelial cells. Nucleic Acids Res  2009; 37(11): 3821-7.
 [http://dx.doi.org/10.1093/nar/gkp255] [PMID: 19386621]

[150]
Labbaye C, Spinello I, Quaranta MT, et al. A three-step pathway comprising PLZF/miR-146a/CXCR4 controls megakaryopoiesis. Nat Cell Biol  2008; 10(7): 788-801.
 [http://dx.doi.org/10.1038/ncb1741] [PMID: 18568019]

[151]
Nguyen LS, Fregeac J, Bole-Feysot C, et al. Role of miR-146a in neural stem cell differentiation and neural lineage determination: relevance for neurodevelopmental disorders. Mol Autism  2018; 9(1): 38.
 [http://dx.doi.org/10.1186/s13229-018-0219-3] [PMID: 29951184]

[152]
Bagga S, Bracht J, Hunter S, et al. Regulation by let-7 and lin-4 miRNAs Results in Target mRNA Degradation. Cell  2005; 122(4): 553-63.
 [http://dx.doi.org/10.1016/j.cell.2005.07.031] [PMID: 16122423]

[153]
Großhans H, Johnson T, Reinert KL, Gerstein M, Slack FJ. The temporal patterning microRNA let-7 regulates several transcription factors at the larval to adult transition in C. elegans. Dev Cell  2005; 8(3): 321-30.
 [http://dx.doi.org/10.1016/j.devcel.2004.12.019] [PMID: 15737928]

[154]
Van Wynsberghe PM, Kai ZS, Massirer KB, Burton VH, Yeo GW, Pasquinelli AE. LIN-28 co-transcriptionally binds primary let-7 to regulate miRNA maturation in Caenorhabditis elegans. Nat Struct Mol Biol  2011; 18(3): 302-8.
 [http://dx.doi.org/10.1038/nsmb.1986] [PMID: 21297634]

[155]
Borzi C, Calzolari L, Centonze G, Milione M, Sozzi G, Fortunato O. mir-660-p53-mir-486 network: A new key regulatory pathway in lung tumorigenesis. Int J Mol Sci  2017; 18(1): 222.
 [http://dx.doi.org/10.3390/ijms18010222] [PMID: 28124991]

[156]
O’Connell RM, Rao DS, Chaudhuri AA, et al. Sustained expression of microRNA-155 in hematopoietic stem cells causes a myeloproliferative disorder. J Exp Med  2008; 205(3): 585-94.
 [http://dx.doi.org/10.1084/jem.20072108] [PMID: 18299402]

[157]
Fukao T, Fukuda Y, Kiga K, et al. An evolutionarily conserved mechanism for microRNA-223 expression revealed by microRNA gene profiling. Cell  2007; 129(3): 617-31.
 [http://dx.doi.org/10.1016/j.cell.2007.02.048] [PMID: 17482553]

[158]
Pulikkan JA, Dengler V, Peramangalam PS, et al. Cell-cycle regulator E2F1 and microRNA-223 comprise an autoregulatory negative feedback loop in acute myeloid leukemia. Blood  2010; 115(9): 1768-78.
 [http://dx.doi.org/10.1182/blood-2009-08-240101] [PMID: 20029046]

[159]
Li T, Morgan MJ, Choksi S, Zhang Y, Kim YS, Liu Z. MicroRNAs modulate the noncanonical transcription factor NF-κB pathway by regulating expression of the kinase IKKα during macrophage differentiation. Nat Immunol  2010; 11(9): 799-805.
 [http://dx.doi.org/10.1038/ni.1918] [PMID: 20711193]

[160]
Eiring AM, Harb JG, Neviani P, et al. miR-328 functions as an RNA decoy to modulate hnRNP E2 regulation of mRNA translation in leukemic blasts. Cell  2010; 140(5): 652-65.
 [http://dx.doi.org/10.1016/j.cell.2010.01.007] [PMID: 20211135]

[161]
Pulikkan JA, Peramangalam PS, Dengler V, et al. C/EBPα regulated microRNA-34a targets E2F3 during granulopoiesis and is down-regulated in AML with CEBPA mutations. Blood  2010; 116(25): 5638-49.
 [http://dx.doi.org/10.1182/blood-2010-04-281600] [PMID: 20889924]
Cite As