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Micromanagers of gene expression: the potentially widespread influence of metazoan microRNAs

Abstract

We propose that the microRNA milieu, unique to each cell type, productively dampens the expression of thousands of mRNAs and provides important context for the evolution of all metazoan mRNA sequences. For genes that should not be expressed in a particular cell type, protein output is lowered to inconsequential levels. For other genes, dosage is adjusted in a manner that allows for customized expression in different cell types while achieving a more uniform level within each cell type. In these ways, the microRNAs add an extensive layer of gene control that integrates with transcriptional and other regulatory processes to expand the complexity of metazoan gene expression.

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Figure 1: The combinatorial rheostat analogy.
Figure 2: Three categories of microRNA targets.
Figure 3: The evolutionary pressure that strengthens or weakens mRNA pairing to the microRNAs.

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Acknowledgements

We thank M. Jones-Rhoades, I. Shih, L. Lim, B. Lewis, C. Burge, B. Bartel, H. Lodish and other colleagues for stimulating discussions. MicroRNA research is supported by grants from the National Institutes of Health and the Alexander and Margaret Stewart Trust (D.P.B.) and a grant from the National Science Foundation to H.F. Lodish (C-.Z.C).

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Correspondence to David P. Bartel.

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DATABASES

LocusLink

hbl-1

let-7

lin-4

lin-14

lin-28

lin-41

miR-2

TAIR

ARGONAUTE1

DICER-LIKE1

FURTHER INFORMATION

David Bartel's laboratory

Glossary

KOZAK SEQUENCE

A consensus sequence element within the 5′-untranslated region of eukaryotes that enhances the recognition of a nearby start codon.

RNA INTERFERENCE

(RNAi). Post-transcriptional gene silencing in animals, triggered by dsRNA that corresponds to the target gene. The dsRNA is processed to small interfering RNAs that serve as guide RNAs for the recognition and cleavage of complementary mRNAs. Analogous silencing processes occur in plants, some fungi and other eukaryotes. The molecular machinery of RNAi is also required for RNA-mediated DNA silencing and for the biogenesis and function of microRNAs.

SMALL INTERFERING RNAS

(siRNAs; also known as short interfering RNAs). Small RNAs, typically 21–23 nucleotides in length, that act as guide RNAs to specify the cleavage of mRNAs during RNA interference (RNAi). Heterochromatic siRNAs are also implicated in the RNAi-related process that silences DNA. siRNAs differ from microRNAs in several respects: they are generally not conserved in evolution, they naturally come from long RNA duplexes that are processed such that many siRNA species come from each duplex and they are typically derived from mRNAs, transposons, viruses or heterochromatic DNA, all of which can be targeted for silencing by the siRNAs.

SPLICEOSOME

The intron-removing apparatus in eukaryotic nuclei.

U6 SNRNA

One of five integral RNA components of spliceosomes, U6 snRNAs are riboprotein complexes that assemble on primary transcripts of eukaryotic mRNAs to catalyse the excision of introns.

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Bartel, D., Chen, CZ. Micromanagers of gene expression: the potentially widespread influence of metazoan microRNAs. Nat Rev Genet 5, 396–400 (2004). https://doi.org/10.1038/nrg1328

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