MicroRNAs and Human Disease


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.



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Further Reading

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

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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.

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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]