MicroRNAs and Human Disease

Abstract

Micro ribonucleic acids (miRNAs) are a group of small, noncoding RNA molecules 20–22 nucleotides (nt) in length that are predicted to control the activity of approximately 30% of all protein‐coding genes in mammals. Their importance in fine‐tuning the regulation of gene expression is evident in the fact that miRNA dysregulation plays important roles in many diseases, including cancer, cardiovascular disease, diabetes, mental disorders and viral infection. As our understanding of the biogenesis and mechanisms of action of miRNAs has grown over the past decade, so has the promise that miRNAs can serve as valuable therapeutic targets for a large number of diseases. Thus, using miRNAs as therapeutics is the next frontier for the study of these molecules in human disease.

Key Concepts:

  • The first miRNA (lin‐4) was identified in nematodes in 1993.

  • miRNAs are now predicted to control the activity of approximately 30% of all protein‐coding genes in mammals.

  • miRNAs regulate gene expression at the posttranscriptional level.

  • miRNAs function by targeting a specific region of a target mRNA typically located in the 3′ untranslated region (UTR).

  • miRNAs can function indirectly as either tumour suppressors or oncogenes.

  • miR‐1 was observed to play a key role in cardiomyocyte differentiation.

  • miR‐375 regulates insulin secretion by targeting myotrophin.

  • Expression of miR‐107 decreases early in Alzheimer disease.

  • miR‐122 is essential for hepatitis C virus (HCV) replication in the liver.

Keywords: microRNA; cancer; cardiovascular; Alzheimer; noncoding; diabetes; virus; disease; RNAi

Figure 1.

miRNA biogenesis. miRNAs transcribed from separate transcription units, that is, under control of their own promoters, are termed intergenic miRNAs. These miRNAs can be expressed as single miRNAs, in which case they are considered monocistronic, but are more commonly located in a joint cluster with other miRNAs, and give rise to polycistronic transcripts. Intronic miRNAs are those located within the introns of other genes, and are therefore under control of the same promoter as the host gene. Their expression tends to be correlated. These miRNAs can be excised from host mRNAs via the RNAi machinery (Drosha) or through cellular splicing events, in which case they are termed miRtrons. miRNAs are processed by RNA polymerase II into primary miRNAs which can range from several hundred to several thousand bases. The resulting primary miRNA, which has a characteristic hairpin structure, is processed in the nucleus by the RNase type III Drosha (and its partner DGCR8) to produce precursor miRNAs (pre‐miRNAs). The precursors are then exported to the cytoplasm by exportin 5 and processed into miRNA duplexes through the action of the cytoplasmic type III RNAse Dicer (and its partner TRBP). Duplexes are then incorporated into the miRNA‐induced silencing complex (miRISC), where they are processed into the mature effector miRNA molecule of ∼22 nt in length. Interaction with the target occurs at the 3′‐UTR or the target, and results in cleavage if the bound miRNA engages in perfect base complementarity with its target. Imperfect complementarity leads to translational repression.

Figure 2.

Regulation by miRNAs. miRNAs typically regulate gene expression by binding to partially complementary target sites in the 3′‐UTR of mRNA, reducing its translation. If the miRNA and mRNA target share perfect complementarity (which is very rare) the mRNA will be cleaved and degraded by the action of Ago2. In most cases, imperfect binding will lead to translational repression, which may occur through a variety of different mechanisms or a joint enforcement of one more of them. Following miRNA binding, target mRNAs may be sequestered to P‐bodies, where abundant deadenylases will shorten the polyA tail of the mRNA, preventing translation. Another mechanism of repression involves prevention of ribosome binding to the 5′ cap, which results in a block of translation initiation. miRNAs can also block the elongation step of translation by inducing secondary structure restrictions which lead to ribosome drop‐off. Finally, miRNAs can also exert their influence by binding directly to open reading frames or 5′‐UTR in a manner similar to traditional 3′‐UTR binding.

close

References

Bazzini AA, Hopp HE, Beachy RN and Asurmendi S (2007) Infection and coaccumulation of tobacco mosaic virus proteins alter microRNA levels, correlating with symptom and plant development. Proceedings of the National Academy of Sciences of the USA 104: 12157–12162.

Beilharz TH, Humphreys DT, Clancy JL et al. (2009) microRNA‐mediated messenger RNA deadenylation contributes to translational repression in mammalian cells. PLoS ONE 4: e6783.

Bendoraite A, Knouf EC, Garg KS et al. (2010) Regulation of miR‐200 family microRNAs and ZEB transcription factors in ovarian cancer: evidence supporting a mesothelial‐to‐epithelial transition. Gynecologic Oncology 116: 117–125.

Bennasser Y, Le SY, Benkirane M and Jeang KT (2005) Evidence that HIV‐1 encodes an siRNA and a suppressor of RNA silencing. Immunity 22: 607–619.

Bhattacharyya SN, Habermacher R, Martine U et al. (2006) Relief of microRNA‐mediated translational repression in human cells subjected to stress. Cell 125: 1111–1124.

Boominathan L (2010) The tumor suppressors p53, p63, and p73 are regulators of microRNA processing complex. PLoS ONE 5: e10615.

Burk U, Schubert J, Wellner U et al. (2008) A reciprocal repression between ZEB1 and members of the miR‐200 family promotes EMT and invasion in cancer cells. EMBO Reports 9: 582–589.

Calin GA, Dumitru CD, Shimizu M et al. (2002) Frequent deletions and down‐regulation of micro‐RNA genes miR15 and miR16 at 13q14 in chronic lymphocytic leukemia. Proceedings of the National Academy of Sciences of the USA 99: 15524–15529.

Calin GA, Sevignani C, Dumitru CD et al. (2004) Human microRNA genes are frequently located at fragile sites and genomic regions involved in cancers. Proceedings of the National Academy of Sciences of the USA 101: 2999–3004.

Chellappan P, Vanitharani R and Fauquet CM (2007) MicroRNA‐binding viral protein interferes with Arabidopsis development. Proceedings of the National Academy of Sciences of the USA 102: 10381–10386.

Chen X, Ba Y, Ma L et al. (2008) Characterization of microRNAs in serum: a novel class of biomarkers for diagnosis of cancer and other diseases. Cell Research 10: 997–1006.

Cimmino A, Calin GA, Fabbri M et al. (2005) miR‐15 and miR‐16 induce apoptosis by targeting BCL2. Proceedings of the National Academy of Sciences of the USA 102: 13944–13949.

Cogswell JP, Ward J, Taylor IA et al. (2008) Identification of miRNA changes in Alzheimer's disease brain and CSF yields putative biomarkers and insights into disease pathways. Journal of Alzheimer's Disease 14: 27–41.

Costinean S, Zanesi N, Pekarsky Y et al. (2006) Pre‐B cell proliferation and lymphoblastic leukemia/high‐grade lymphoma in E(mu)‐miR155 transgenic mice. Proceedings of the National Academy of Sciences of the USA 103: 7024–7029.

Denli AM, Tops BB, Plasterk RH et al. (2004) Processing of primary microRNAs by the microprocessor complex. Nature 432: 231–235.

Eulalio A, Behm‐Ansmant I, Schweizer D and Izaurralde E (2007) P‐body formation is a consequence, not the cause, of RNA‐mediated gene silencing. Molecular and Cellular Biology 27: 3970–3981.

Giraldez AJ, Mishima Y, Rihel J et al. (2006) Zebrafish MiR‐430 promotes deadenylation and clearance of maternal mRNAs. Science 312: 75–79.

Fire A, Xu S, Montgomery MK et al. (1998) Potent and specific genetic interference by double‐stranded RNA in Caenorhabditis elegans. Nature 91: 806–811.

Han MH, Goud S, Song L and Fedoroff N (2004) The Arabidopsis double‐stranded RNA‐binding protein HYL1 plays a role in microRNA‐mediated gene regulation. Proceedings of the National Academy of Sciences of the USA 101: 1093–1098.

Hebert SS, Horre K, Nicolai L et al. (2009) MicroRNA regulation of Alzheimer's amyloid precursor protein expression. Neurobiology of Disease 33: 422–428.

Jiang S, Zhang HW, Lu MH et al. (2010) MicroRNA‐155 functions as an OncomiR in breast cancer by targeting the suppressor of cytokine signaling 1 gene. Cancer Research 70: 3119–3127.

Jopling CL, Yi M, Lancaster AM et al. (2005) Modulation of hepatitis C virus RNA abundance by a liver‐specific microRNA. Science 309: 1577–1581.

Khvorova A, Reynolds A and Jayasena SD (2003) Functional siRNAs and miRNAs exhibit strand bias. Cell 115: 209–216.

Kim YK and Kim VN (2007) Processing of intronic microRNAs. EMBO Journal 26: 775–783.

Lai EC (2002) Micro RNAs are complementary to 3′ UTR sequence motifs that mediate negative post‐transcriptional regulation. Nature Genetics 30: 363–364.

Landthaler M, Yalcin A and Tuschl T (2004) The human DiGeorge syndrome critical region gene 8 and Its D. melanogaster homolog are required for miRNA biogenesis. Current Biology 14: 2162–2167.

Lanford RE, Hildebrandt‐Eriksen ES, Petri A et al. (2010) Therapeutic silencing of microRNA‐122 in primates with chronic hepatitis C virus infection. Science 327: 198–201.

Lee RC, Feinbaum RL and Ambros V (1993) The C. elegans heterochronic gene lin‐4 encodes small RNAs with antisense complementarity to lin‐14. Cell 75: 843–854.

Lewis BP, Burge CB and Bartel DP (2005) Conserved seed pairing, often flanked by adenosines, indicates that thousands of human genes are microRNA targets. Cell 120: 15–20.

Lin J and Cullen BR (2007) Analysis of the interaction of primate retroviruses with the human RNA interference machinery. Journal of Virology 81: 12218–12226.

Lovis P, Gattesco S and Regazzi R (2008a) Regulation of the expression of components of the exocytotic machinery of insulin‐secreting cells by microRNAs. Biological Chemistry 389: 305–312.

Lovis P, Roggli E, Laybutt DR et al. (2008b) Alterations in microRNA expression contribute to fatty acid‐induced pancreatic beta‐cell dysfunction. Diabetes 57: 2728–2736.

Lukiw WJ (2007) Micro‐RNA speciation in fetal, adult and Alzheimer's disease hippocampus. Neuroreport 18: 297–300.

Martin MM, Buckenberger JA, Jiang J et al. (2007) Malana GE, Nuovo GJ, Chotani M, Feldman DS, Schmittgen TD, Elton TS: The human angiotensin II type 1 receptor +1166 A/C polymorphism attenuates microrna‐155 binding. Journal of Biological Chemistry 282: 24262–24269.

Pedersen IM, Cheng G, Wieland S et al. (2007) Interferon modulation of cellular microRNAs as an antiviral mechanism. Nature 449: 919–922.

Petersen CP, Bordeleau ME, Pelletier J and Sharp PA (2006) Short RNAs repress translation after initiation in mammalian cells. Molecular Cell 21: 533–542.

Pillai RS, Artus CG and Filipowicz W (2004) Tethering of human Ago proteins to mRNA mimics the miRNA‐mediated repression of protein synthesis. RNA 10: 1518–1525.

Pillai RS, Bhattacharyya SN, Artus CG et al. (2005) Inhibition of translational initiation by Let‐7 MicroRNA in human cells. Science 309: 1573–1576.

Poy MN, Eliasson L, Krutzfeldt J et al. (2004) A pancreatic islet‐specific microRNA regulates insulin secretion. Nature 432: 226–230.

Prevention CfDCa (2008) National Diabetes Fact Sheet: general information and national estimates on diabetes in the United States, 2007. US Dept of Health and Human Services, CDC 2008.

Rand TA, Ginalski K, Grishin NV and Wang X (2004) Biochemical identification of Argonaute 2 as the sole protein required for RNA‐induced silencing complex activity. Proceedings of the National Academy of Sciences of the USA 101: 14385–14389.

Rao PK, Toyama Y, Chiang HR et al. (2009) Loss of cardiac microRNA‐mediated regulation leads to dilated cardiomyopathy and heart failure. Circulation Research 105: 585–594.

Tavazoie SF, Alarcon C, Oskarsson T et al. (2008) Endogenous human microRNAs that suppress breast cancer metastasis. Nature 451: 147–152.

Tay Y, Zhang J, Thomson AM et al. (2008) MicroRNAs to Nanog, Oct4 and Sox2 coding regions modulate embryonic stem cell differentiation. Nature 455: 1124–1128.

Wang WX, Rajeev BW, Stromberg AJ et al. (2008) The expression of microRNA miR‐107 decreases early in Alzheimer's disease and may accelerate disease progression through regulation of beta‐site amyloid precursor protein‐cleaving enzyme 1. Journal of Neuroscience 28: 1213–1223.

Yang B, Lin H, Xiao J et al. (2007) The muscle‐specific microRNA miR‐1 regulates cardiac arrhythmogenic potential by targeting GJA1 and KCNJ2. Nature Medicine 13: 486–491.

Yin Q, McBride J, Fewell C et al. (2008) MicroRNA‐155 is an Epstein–Barr virus‐induced gene that modulates Epstein–Barr virus‐regulated gene expression pathways. Journal of Virology 82: 5295–5306.

Zhang Y, Li M, Wang H et al. (2009) Profiling of 95 microRNAs in pancreatic cancer cell lines and surgical specimens by real‐time PCR analysis. World Journal of Surgery 33: 698–709.

Zhao Y, Ransom JF, Li A et al. (2007) Dysregulation of cardiogenesis, cardiac conduction, and cell cycle in mice lacking miRNA‐1‐2. Cell 129: 303–317.

Zhao Y, Samal E and Srivastava D (2005) Serum response factor regulates a muscle‐specific microRNA that targets Hand2 during cardiogenesis. Nature 436: 214–220.

Further Reading

Appasani K (2008) MicroRNAs: From Basic Science to Disease Biology. Cambridge, UK: Cambridge University Press.

Liu N and Olson EN (2010) MicroRNA regulatory networks in cardiovascular development. Developmental Cell 18: 510–525. Review.

Newman MA and Hammond SM (2010) Emerging paradigms of regulated microRNA processing. Genes & Development 24: 1086–1092. Review.

Ouellet DL, Plante I, Barat C et al. (2009) Emergence of a complex relationship between HIV‐1 and the microRNA pathway. Methods in Molecular Biology 487: 415–433. Review.

Pandey AK, Agarwal P, Kaur K and Datta M (2009) MicroRNAs in diabetes: tiny players in big disease. Cell Physiology and Biochemistry 23: 221–232. Review.

Roshan R, Ghosh T, Scaria V and Pillai B (2009) MicroRNAs: novel therapeutic targets in neurodegenerative diseases. Drug Discovery Today 14: 1123–1129. Review.

Ryan BM, Robles AI and Harris CC (2010) Genetic variation in microRNA networks: the implications for cancer research. Nature Reviews. Cancer 10: 389–402 Review.

Contact Editor close
Submit a note to the editor about this article by filling in the form below.

* Required Field

How to Cite close
Marin‐Muller, Christian, Yao, Qizhi, and Chen, Changyi(Oct 2010) MicroRNAs and Human Disease. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0021433]