MicroRNAs: small RNAs with a big role in gene regulation

A Correction to this article was published on 01 August 2004

Key Points

  • MicroRNAs (miRNAs) are a family of 21–25-nucleotide small RNAs that negatively regulate gene expression at the post-transcriptional level.

  • The founding members of the miRNA family, lin-4 and let-7, were identified through genetic screens for defects in the temporal regulation of Caenorhabditis elegans larval development.

  • Owing to genome-wide cloning efforts, hundreds of miRNAs have now been identified in almost all metazoans, including flies, plants and mammals.

  • MiRNAs exhibit temporally and spatially regulated expression patterns during diverse developmental and physiological processes.

  • Most of the miRNAs that have been characterized so far seem to regulate aspects of development, including larval developmental transitions and neuronal development in C. elegans, growth control and apoptosis in Drosophila melanogaster, haematopoietic differentiation in mammals, and leaf development, flower development and embryogenesis in Arabidopsis thaliana.

  • The majority of the animal miRNAs that have been characterized so far affect protein synthesis from their target mRNAs. On the other hand, most of the plant miRNAs studied so far direct the cleavage of their targets.

  • The degree of complementarity between a miRNA and its target, at least in part, determines the regulatory mechanism.

  • In animals, primary transcripts of miRNAs are processed sequentially by two RNase-III enzymes, Drosha and Dicer, into a small, imperfect dsRNA duplex (miRNA:miRNA*) that contains both the mature miRNA strand and its complementary strand (miRNA*). Relative instability at the 5′ end of the mature miRNA leads to the asymmetric assembly of the mature miRNA into the effector complex, the RNA-induced silencing complex (RISC).

  • Ago proteins are a key component of the RISC. Multiple Ago homologues in various metazoan genomes indicate the existence of multiple RISCs that carry out related but specific biological functions.

  • Bioinformatic prediction of miRNA targets has provided an important tool to explore the functions of miRNAs. However, the overall success rate of such predictions remains to be determined by experimental validation.


MicroRNAs are a family of small, non-coding RNAs that regulate gene expression in a sequence-specific manner. The two founding members of the microRNA family were originally identified in Caenorhabditis elegans as genes that were required for the timed regulation of developmental events. Since then, hundreds of microRNAs have been identified in almost all metazoan genomes, including worms, flies, plants and mammals. MicroRNAs have diverse expression patterns and might regulate various developmental and physiological processes. Their discovery adds a new dimension to our understanding of complex gene regulatory networks.

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Figure 1: The molecular hallmarks of lin-4, the founding member of the microRNA family.
Figure 2: The current model for the biogenesis and post-transcriptional suppression of microRNAs and small interfering RNAs.
Figure 3: The structure and function of the Dicer family.


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We thank J. M. Silva, A. M. Denli, L. E. Palmer, J. Liu, P. J. Paddison and E. P. Murchson for stimulating discussions and helpful input. We also thank J. C. Duffy for help with the figures. We are particularly grateful to M. A. Carmell and Z. Xuan, who provided valuable comments and suggestions in the preparation of this manuscript. G.J.H. is supported by an Innovator Award from the US Army Breast Cancer Research Program and by grants from the National Institutes of Health. L.H. is a Helen Hay Whitney Fellow.

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Correspondence to Gregory J. Hannon.

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hbl-1 (lin-57)


















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PHYLIP programs



(RNAi). A form of post-transcriptional gene silencing, in which dsRNA induces degradation of the homologous mRNA, mimicking the effect of the reduction, or loss, of gene activity.


As applied to molecular phylogenies, nucleotide or amino-acid sites are sampled randomly, with replacement, and a new tree is constructed. This is repeated many times and the frequency of appearance of a particular node among the bootstrap trees is viewed as a support (confidence) value for deciding on the significance of that node.


A cell line that is isolated from dissociated Drosophila melanogaster embryos. The cell line is phagocytic, which might contribute to its susceptibility to RNAi.


A functional unit of protein synthesis that consists of several ribosomes that are attached along the length of a single molecule of mRNA.


The undifferentiated tissue at the tips of stems and roots in which new cell division is concentrated.


A family of transposable elements that are widely used as the basis of tools for mutating and manipulating the Drosophila genome.


A sac-like structure of a mature third instar fly larva, which will give rise to the adult wing.


The reproductive backbone that displays the flowers.

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He, L., Hannon, G. MicroRNAs: small RNAs with a big role in gene regulation. Nat Rev Genet 5, 522–531 (2004). https://doi.org/10.1038/nrg1379

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