Argonaute-associated short introns are a novel class of gene regulators.

Thomas B Hansen,Morten T Venø,Trine I Jensen,Jørgen Kjems,Christian K Damgaard,Anne Schaefer

doi:10.1038/ncomms11538

Thomas B Hansen, Morten T Venø + Show 4 more

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https://doi.org/10.1038/ncomms11538

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Abstract

MicroRNAs (miRNAs) are short (∼22 nucleotides) regulators of gene expression acting by direct base pairing to 3′-UTR target sites in messenger RNAs. Mature miRNAs are produced by two sequential endonucleolytic cleavages facilitated by Drosha in the nucleus and Dicer in the cytoplasm. A subclass of miRNAs, termed mirtrons, derives from short introns and enters the miRNA biogenesis pathway as Dicer substrates. Here we uncover a third biogenesis strategy that, similar to mirtron biogenesis, initiates from short introns but bypasses Dicer cleavage. These short introns (80–100 nucleotides), coined agotrons, are associated with and stabilized by Argonaute (Ago) proteins in the cytoplasm. Some agotrons are completely conserved in mammalian species, suggesting that they are functionally important. Furthermore, we demonstrate that the agotrons are capable of repressing mRNAs with seed-matching target sequences in the 3′-UTR. These data provide evidence for a novel RNA regulator of gene expression, which bypasses the canonical miRNA biogenesis machinery.

Highlights

MicroRNAs are short (B22 nucleotides) regulators of gene expression acting by direct base pairing to 30-untranslated region (30-UTR) target sites in messenger RNAs
The miRNA is incorporated into the RNA-induced silencing complex (RISC) and directs the binding to specific regions in the 30-untranslated region (30-UTR) of mRNAs by Watson–Crick base pairing between the miRNA seed and the target[2]
While analysing the Ago2-CLIP data set from mouse forebrain neurons[9], we noticed a high density of long reads exceeding 30 nucleotides in length across short introns in Pkd[1], Acadvl and Kifc[2] genes (Fig. 1a–c)

Summary

Introduction

MicroRNAs (miRNAs) are short (B22 nucleotides) regulators of gene expression acting by direct base pairing to 30-UTR target sites in messenger RNAs. We uncover a third biogenesis strategy that, similar to mirtron biogenesis, initiates from short introns but bypasses Dicer cleavage These short introns (80–100 nucleotides), coined agotrons, are associated with and stabilized by Argonaute (Ago) proteins in the cytoplasm. We demonstrate that the agotrons are capable of repressing mRNAs with seed-matching target sequences in the 30-UTR These data provide evidence for a novel RNA regulator of gene expression, which bypasses the canonical miRNA biogenesis machinery. The miRNA is incorporated into the RNA-induced silencing complex (RISC) and directs the binding to specific regions in the 30-untranslated region (30-UTR) of mRNAs by Watson–Crick base pairing between the miRNA seed (position 2–8) and the target[2]. Agotrons induce target repression in an miRNA-like manner and we identify endogenous targets for the highly conserved agotron in the last intron of the Pkd[1] gene

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