MicroRNA Expression: Protein Participants in MicroRNA Regulation

  • Valeria M. King
  • Glen M. BorchertEmail author
Part of the Methods in Molecular Biology book series (MIMB, volume 1617)


MiRNAs are ~20 nt small RNAs that regulate networks of proteins using a seed region of nucleotides 2–8 to complement the 3′ UTR of target mRNAs. The biogenesis and function of miRNAs as translational repressors is facilitated by protein counterparts that process primary and precursor miRNAs to maturity (Drosha/DCGR8 and Dicer/TRBP respectively) and incorporate miRNAs into the protein complex RISC to recognize and repress target mRNAs (RISC proteins: Ago/TRBP1/TRBP2/DICER). Similarly, siRNAs through comparable mechanisms are loaded into the protein complex RITS to heterochromatin formation of DNA and suppress transcription of particular genes. MiRNAs are also regulated themselves through many different pathways including transcriptional regulation, post-transcriptional RNA editing, and RNA tailing. Dysregulation of miRNAs and the protein participants that mature them are implicated in the development of a number of diseases, tumorigenesis, and arrested development of embryonic cells. In this chapter, we will explore the biosynthesis, function, and regulation of miRNAs.

Key words

Dicer Drosha miRNA mRNA Protein RISC Regulation 


  1. 1.
    Graves P, Zeng Y (2012) Biogenesis of mammalian microRNAs: a global view. Genomics Proteomics Bioinformatics 10:239–245. doi: 10.1016/j.gpb.2012.06.004 CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    Ha M, Kim VN (2014) Regulation of microRNA biogenesis. Nat Rev Mol Cell Biol 15:509–524. doi: 10.1038/nrm3838 CrossRefPubMedGoogle Scholar
  3. 3.
    Krützfeldt J, Stoffel M (2006) MicroRNAs: a new class of regulatory genes affecting metabolism. Cell Metab 4:9–12. doi: 10.1016/j.cmet.2006.05.009 CrossRefPubMedGoogle Scholar
  4. 4.
    Nakahara K, Carthew RW (2004) Expanding roles for miRNAs and siRNAs in cell regulation. Curr Opin Cell Biol 16:127–133. doi: 10.1016/ CrossRefPubMedGoogle Scholar
  5. 5.
    Lee RC, Feinbaum RL, Ambros V (1993) The C. elegans heterochronic gene lin-4 encodes small RNAs with antisense complementarity to lin-14. Cell 75:843–854. doi: 10.1016/0092-8674(93)90529-Y CrossRefPubMedGoogle Scholar
  6. 6.
    Lee RC, Ambros V (2001) An extensive class of small RNAs in Caenorhabditis elegans. Science 294:862–864. doi: 10.1126/science.1065329 CrossRefPubMedGoogle Scholar
  7. 7.
    miRBase. Accessed 11 Oct 2015
  8. 8.
    Li M, Marin-Muller C, Bharadwaj U et al (2009) MicroRNAs: control and loss of control in human physiology and disease. World J Surg 33:667–684. doi: 10.1007/s00268-008-9836-x CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Yue S-B, Trujillo RD, Tang Y et al (2011) Loop nucleotides control primary and mature miRNA function in target recognition and repression. RNA Biol 8:1115–1123. doi: 10.4161/rna.8.6.17626 CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Roberts JT, Cooper EA, Favreau CJ et al (2013) Continuing analysis of microRNA origins: formation from transposable element insertions and noncoding RNA mutations. Mob Genet Elements 3:e27755. doi: 10.4161/mge.27755 CrossRefPubMedGoogle Scholar
  11. 11.
    Roberts JT, Cardin SE, Borchert GM (2014) Burgeoning evidence indicates that microRNAs were initially formed from transposable element sequences. Mob Genet Elements 4:e29255. doi: 10.4161/mge.29255 CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Filshtein TJ, Mackenzie CO, Dale MD et al (2012) OrbId: origin-based identification of microRNA targets. Mob Genet Elements 2:184–192. doi: 10.4161/mge.21617 CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Kobayashi H, Tomari Y (2015) RISC assembly: coordination between small RNAs and Argonaute proteins. Biochim Biophys Acta. doi: 10.1016/j.bbagrm.2015.08.007 Google Scholar
  14. 14.
    Ouellet DL, Perron MP, Gobeil L-A, Plante P, Provost P (2006) MicroRNAs in gene regulation: when the smallest governs it all. J Biomed Biotechnol 2006:20. doi: 10.1155/JBB/2006/69616 CrossRefGoogle Scholar
  15. 15.
    Parker GS, Maity TS, Bass BL (2008) dsRNA binding properties of RDE-4 and TRBP reflect their distinct roles in RNAi. J Mol Biol 384:967–979. doi: 10.1016/j.jmb.2008.10.002 CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Bahubeshi A, Tischkowitz M, Foulkes WD (2011) miRNA processing and human cancer: DICER1 cuts the mustard. Sci Transl Med 3:111ps46. doi: 10.1126/scitranslmed.3002493 CrossRefPubMedGoogle Scholar
  17. 17.
    Agrawal N, Dasaradhi PVN, Mohmmed A et al (2003) RNA interference: biology, mechanism, and applications. Microbiol Mol Biol Rev 67:657–685. doi: 10.1128/MMBR.67.4.657-685.2003 CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Krol J, Busskamp V, Markiewicz I et al (2010) Characterizing light-regulated retinal microRNAs reveals rapid turnover as a common property of neuronal microRNAs. Cell 141:618–631. doi: 10.1016/j.cell.2010.03.039 CrossRefPubMedGoogle Scholar
  19. 19.
    Zhang B, Wang Q, Pan X (2007) MicroRNAs and their regulatory roles in animals and plants. J Cell Physiol 210:279–289. doi: 10.1002/jcp.20869 CrossRefPubMedGoogle Scholar
  20. 20.
    Verdel A, Jia S, Gerber S et al (2004) RNAi-mediated targeting of heterochromatin by the RITS complex. Science 303:672–676. doi: 10.1126/science.1093686 CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Lam JKW, Chow MYT, Zhang Y, Leung SWS (2015) siRNA versus miRNA as therapeutics for gene silencing. Mol Ther Nucleic Acids 4:e252. doi: 10.1038/mtna.2015.23 CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Ivanova AV, Bonaduce MJ, Ivanov SV, Klar AJ (1998) The chromo and SET domains of the Clr4 protein are essential for silencing in fission yeast. Nat Genet 19:192–195. doi: 10.1038/566 CrossRefPubMedGoogle Scholar
  23. 23.
    Cai Y, Yu X, Hu S, Yu J (2009) A brief review on the mechanisms of miRNA regulation. Genomics Proteomics Bioinformatics 7:147–154. doi: 10.1016/S1672-0229(08)60044-3 CrossRefPubMedGoogle Scholar
  24. 24.
    Lee C-T, Risom T, Strauss WM (2006) MicroRNAs in mammalian development. Birth Defects Res C Embryo Today 78:129–139. doi: 10.1002/bdrc.20072 CrossRefPubMedGoogle Scholar
  25. 25.
    Xhemalce B, Robson SC, Kouzarides T (2012) Human RNA methyltransferase BCDIN3D regulates microRNA processing. Cell 151:278–288. doi: 10.1016/j.cell.2012.08.041 CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    He X-X, Kuang S-Z, Liao J-Z et al (2015) The regulation of microRNA expression by DNA methylation in hepatocellular carcinoma. Mol Biosyst 11:532–539. doi: 10.1039/C4MB00563E CrossRefPubMedGoogle Scholar
  27. 27.
    Schanen BC, Li X (2011) Transcriptional regulation of mammalian miRNA genes. Genomics 97:1–6. doi: 10.1016/j.ygeno.2010.10.005 CrossRefPubMedGoogle Scholar
  28. 28.
    Boyer LA, Lee TI, Cole MF et al (2005) Core transcriptional regulatory circuitry in human embryonic stem cells. Cell 122:947–956. doi: 10.1016/j.cell.2005.08.020 CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Marson A, Levine SS, Cole MF et al (2008) Connecting microRNA genes to the core transcriptional regulatory circuitry of embryonic stem cells. Cell 134:521–533. doi: 10.1016/j.cell.2008.07.020 CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Kanellopoulou C (2005) Dicer-deficient mouse embryonic stem cells are defective in differentiation and centromeric silencing. Genes Dev 19:489–501. doi: 10.1101/gad.1248505 CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Sun G, Yan J, Noltner K et al (2009) SNPs in human miRNA genes affect biogenesis and function. RNA 15:1640–1651. doi: 10.1261/rna.1560209 CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Lee YS, Nakahara K, Pham JW et al (2004) Distinct roles for Drosophila Dicer-1 and Dicer-2 in the siRNA/miRNA silencing pathways. Cell 117:69–81. doi: 10.1016/S0092-8674(04)00261-2 CrossRefPubMedGoogle Scholar
  33. 33.
    Yang W, Chendrimada TP, Wang Q et al (2005) Modulation of microRNA processing and expression through RNA editing by ADAR deaminases. Nat Struct Mol Biol 13:13–21. doi: 10.1038/nsmb1041 CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Blow MJ, Grocock RJ, van Dongen S et al (2006) RNA editing of human microRNAs. Genome Biol 7:R27. doi: 10.1186/gb-2006-7-4-r27 CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Ameres SL, Zamore PD (2013) Diversifying microRNA sequence and function. Nat Rev Mol Cell Biol 14:475–488. doi: 10.1038/nrm3611 CrossRefPubMedGoogle Scholar
  36. 36.
    Pasquinelli AE, Reinhart BJ, Slack F et al (2000) Conservation of the sequence and temporal expression of let-7 heterochronic regulatory RNA. Nature 408:86–89. doi: 10.1038/35040556 CrossRefPubMedGoogle Scholar
  37. 37.
    Suh M-R, Lee Y, Kim JY et al (2004) Human embryonic stem cells express a unique set of microRNAs. Dev Biol 270:488–498. doi: 10.1016/j.ydbio.2004.02.019 CrossRefPubMedGoogle Scholar
  38. 38.
    Katoh T, Sakaguchi Y, Miyauchi K et al (2009) Selective stabilization of mammalian microRNAs by 3′ adenylation mediated by the cytoplasmic poly(A) polymerase GLD-2. Genes Dev 23:433–438. doi: 10.1101/gad.1761509 CrossRefPubMedPubMedCentralGoogle Scholar
  39. 39.
    Backes S, Shapiro JS, Sabin LR et al (2012) Degradation of host MicroRNAs by poxvirus poly(A) polymerase reveals terminal RNA methylation as a protective antiviral mechanism. Cell Host Microbe 12:200–210. doi: 10.1016/j.chom.2012.05.019 CrossRefPubMedPubMedCentralGoogle Scholar
  40. 40.
    Chatterjee S, Fasler M, Büssing I, Grosshans H (2011) Target-mediated protection of endogenous microRNAs in C. elegans. Dev Cell 20:388–396. doi: 10.1016/j.devcel.2011.02.008 CrossRefPubMedGoogle Scholar
  41. 41.
    Rüegger S, Großhans H (2012) MicroRNA turnover: when, how, and why. Trends Biochem Sci 37:436–446. doi: 10.1016/j.tibs.2012.07.002 CrossRefPubMedGoogle Scholar
  42. 42.
    Ramachandran V, Chen X (2008) Degradation of microRNAs by a family of exoribonucleases in Arabidopsis. Science 321:1490–1492. doi: 10.1126/science.1163728 CrossRefPubMedPubMedCentralGoogle Scholar
  43. 43.
    Suzuki HI, Arase M, Matsuyama H et al (2011) MCPIP1 ribonuclease antagonizes dicer and terminates MicroRNA biogenesis through precursor microRNA degradation. Mol Cell 44:424–436. doi: 10.1016/j.molcel.2011.09.012 CrossRefPubMedGoogle Scholar
  44. 44.
    Cazalla D, Yario T, Steitz JA (2010) Down-regulation of a host microRNA by a Herpesvirus saimiri noncoding RNA. Science 328:1563–1566. doi: 10.1126/science.1187197 CrossRefPubMedPubMedCentralGoogle Scholar
  45. 45.
    Lee S, Song J, Kim S et al (2013) Selective degradation of host MicroRNAs by an intergenic HCMV noncoding RNA accelerates virus production. Cell Host Microbe 13:678–690. doi: 10.1016/j.chom.2013.05.007 CrossRefPubMedGoogle Scholar
  46. 46.
    Cesana M, Cacchiarelli D, Legnini I et al (2011) A long noncoding RNA controls muscle differentiation by functioning as a competing endogenous RNA. Cell 147:358–369. doi: 10.1016/j.cell.2011.09.028 CrossRefPubMedPubMedCentralGoogle Scholar
  47. 47.
    Patterson D (2015) A significant percentage of small nucleolar RNAs are processed into microRNAs. Univeraity of South AlabamaGoogle Scholar

Copyright information

© Springer Science+Business Media LLC 2017

Authors and Affiliations

  1. 1.Department of BiologyUniversity of South AlabamaMobileUSA
  2. 2.Department of PharmacologyUniversity of South AlabamaMobileUSA

Personalised recommendations