MicroRNAs (miRNAs) are small non-coding RNAs that function as guide molecules in RNA silencing.
Biogenesis of miRNA is under tight temporal and spatial control.
Dysregulation of miRNA is associated with many human diseases, particularly cancer and neurodevelopmental disorders.
Regulation takes place at multiple levels including transcription, Drosha processing, Dicer processing, RNA editing, RNA methylation, uridylation, adenylation, Argonaute modification and RNA decay.
This Review summarizes our current understanding of how miRNAs are made and regulated, with a focus on animal systems.
MicroRNAs (miRNAs) are small non-coding RNAs that function as guide molecules in RNA silencing. Targeting most protein-coding transcripts, miRNAs are involved in nearly all developmental and pathological processes in animals. The biogenesis of miRNAs is under tight temporal and spatial control, and their dysregulation is associated with many human diseases, particularly cancer. In animals, miRNAs are ∼22 nucleotides in length, and they are produced by two RNase III proteins — Drosha and Dicer. miRNA biogenesis is regulated at multiple levels, including at the level of miRNA transcription; its processing by Drosha and Dicer in the nucleus and cytoplasm, respectively; its modification by RNA editing, RNA methylation, uridylation and adenylation; Argonaute loading; and RNA decay. Non-canonical pathways for miRNA biogenesis, including those that are independent of Drosha or Dicer, are also emerging.
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The authors are grateful to the members of their laboratory for helpful discussions and comments. Work in the authors laboratory was supported by the Research Center Programme (EM1402) of the Institute for Basic Science IBS) from the Ministry of Science, Information and Communication Technology (ICT) and Future Planning of Korea (M.H. and V.N.K.).
The authors declare no competing financial interests.
- Argonaute family proteins
(AGO family proteins). Proteins that associate with small RNAs and function as effectors in RNA silencing. AGO proteins carry two characteristic domains — PIWI (an endoribonuclease domain) and PAZ (PIWI–AGO–ZWILLE; the 3′ end-binding module).
- PIWI-interacting RNA
(piRNA). Small silencing RNAs (24–30 nucleotides long) that bind PIWI clade Argonaute proteins in animals and silence germline transposons. They are thought to derive from single-stranded RNA precursors and do not require RNase III enzymes for their maturation.
The stage of meiotic prophase that immediately follows the zygotene. It is characterized by paired chromosomes that are condensed and visibly divided into chromatids, and by the occurrence of crossing-over.
- Let-7 family
The let-7 gene was initially discovered as an essential developmental gene in Caenorhabditis elegans and, later, as one of the first two microRNAs (miRNAs). The let-7 miRNA family is highly conserved throughout bilaterian animals, and it suppresses cell proliferation and promotes cell differentiation. It is also a tumour suppressor.
(Chromatin immunoprecipitation followed by sequencing). A method used to analyse protein interactions with DNA. It combines ChIP with parallel DNA sequencing to identify the binding sites of DNA-associated proteins.
- DiGeorge syndrome
An autosomal recessive genetic disorder caused by a deletion in chromosome 22 that is commonly associated with heart defects, poor immune system function, a cleft palate and behavioural disorders.
- RNA editing
A molecular process through which some cells make discrete changes to specific nucleotide sequences within an RNA molecule after it has been generated by the RNA polymerase. Editing events may include the insertion, deletion and substitution of nucleotides within the edited RNA molecule.
- RNA-induced silencing complex
(RISC). A ribonucleoprotein complex that consists of a small RNA guide strand bound to an Argonaute protein. RISC mediates all RNA-silencing pathways, and it can also include auxiliary proteins that extend or modify its function.
- RISC-loading complex
(RLC). A protein complex containing Dicer, a double-stranded-RNA-binding protein, an Argonaute (AGO) protein and potentially other proteins that are required for loading of small RNAs onto the AGO protein.
- Processing bodies
(P-bodies). Distinct foci within the cytoplasm of the eukaryotic cell that consist of many enzymes involved in mRNA turnover. They are thought to be sites for translational suppression and/or mRNA decay, and to be involved in RNA silencing. Some mRNAs can exit P-bodies and reinitiate translation.
- Terminal uridylyl transferases
Nucleotidyl transferases that covalently add one or more UMP moieties from UTP to the 3′-OH group of an RNA substrate in a template-independent manner.
- Short hairpin RNAs
Sequences of RNA that have a tight hairpin turn that can be processed by Dicer.
- Small nucleolar RNAs
(snoRNAs). A class of small RNA molecules that primarily guide chemical modifications of other RNAs. This mainly includes rRNAs, tRNAs and small nuclear RNAs.
A transposable element that replicates through an RNA intermediate, which is converted by a reverse transcriptase to cDNA. The cDNA can be inserted into genomic DNA, which increases the number of copies of the retrotransposon in the genome.
A short (∼300 bp long) stretch of repetitive elements that are classified as short interspersed elements among the class of repetitive DNA elements. Alu elements of different kinds occur in large numbers in primate genomes, accounting for over 10% of the human genome.
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Ha, M., Kim, V. Regulation of microRNA biogenesis. Nat Rev Mol Cell Biol 15, 509–524 (2014). https://doi.org/10.1038/nrm3838
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