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  • Review Article
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RNA regulons: coordination of post-transcriptional events

Nature Reviews Genetics volume 8, pages 533–543 (2007)Cite this article

Key Points

  • Transcription is surprisingly stochastic, yet protein production is precise, indicating the importance of post-transcriptional events in the regulation of gene expression.

  • Transcription and translation are not directly coupled in eukaryotic cells, but intervening steps between them help to coordinate protein biosynthesis.

  • RNA-binding proteins (RBPs) co-regulate functionally related mRNAs in ribonucleoprotein (RNP) modules at the steps of splicing, export, stability, localization and translation.

  • Genome-wide methods identified subsets of functionally related mRNAs that associate with RBPs forming 'RNA operons', which drive the coordinated expression of these mRNAs. Some of these mRNAs undergo simultaneous decay, whereas some are translationally co-regulated by polysomes.

  • Each mRNA can be co-regulated with others in multiple combinations; such structures of higher-order coordination can be defined as RNA regulons.

  • RNA regulons dynamically exchange specific mRNAs during proliferation, differentiation, genotoxic treatments or biological cycles.

  • Several RBPs are dysregulated and some mRNAs are defective in human diseases, indicating that mRNA regulons might be implicated in many pathological processes.

Abstract

Recent findings demonstrate that multiple mRNAs are co-regulated by one or more sequence-specific RNA-binding proteins that orchestrate their splicing, export, stability, localization and translation. These and other observations have given rise to a model in which mRNAs that encode functionally related proteins are coordinately regulated during cell growth and differentiation as post-transcriptional RNA operons or regulons, through a ribonucleoprotein-driven mechanism. Here I describe several recently discovered examples of RNA operons in budding yeast, fruitfly and mammalian cells, and their potential importance in processes such as immune response, oxidative metabolism, stress response, circadian rhythms and disease. I close by considering the evolutionary wiring and rewiring of these combinatorial post-transcriptional gene-expression networks.

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Figure 1: Interconnected steps of post-transcriptional regulation and its potential coordination.
Figure 2: Coordination of subsets of eukaryotic mRNAs from transcription to translation.
Figure 3: Formation and dynamics of ribonucleoprotein (RNP) complexes.
Figure 4: Dynamics of post-transcriptional co-regulation.
Figure 5: Model of the Puf3 RNA operon.
Figure 6: Evolutionary wiring and rewiring of RNA–protein interactions.

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  1. Department of Molecular Genetics & Microbiology, Duke University Medical Center, Box 3020, Durham, 27710, North Carolina, USA

    Jack D. Keene

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RNA regulons: coordination of post-transcriptional events. Nature Reviews Genetics 8, 533–543 (2007); doi:10.1038/nrg2111

J.D.K. holds stock in Ribonomics, Inc., a company that owns patents for the RIP-chip technology.

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Glossary

RNA operon

A ribonucleoprotein structure in which multiple mRNAs are coordinately regulated by RNA-binding proteins and small non-coding RNAs. The combination of multiple mRNAs in an RNA operon can change dynamically following biological perturbations.

Gene-expression neighbourhoods

Chromosomal domains containing 15–30 tandem genes that are expressed together owing to localized chromatin modifications.

RIP–chip

A method that involves immunoprecipitation of an endogenous or tagged RNA-binding protein followed by a microarray analysis or sequencing to identify its associated RNAs.

En masse nuclear run-on assay

A method in which newly synthesized mRNAs are dynamically radiolabelled in isolated nuclei before they are post-transcriptionally processed. The transcript levels are then measured by microarray analysis.

Spindle body

A microtubule-organizing region, found in yeasts and other fungi, that is thought to be homologous to the centrosome of mammals.

Polysome gradients

A method in which velocity centrifugation on sucrose gradients is used to separate ribonucleoprotein complexes from ribosomes and ribosomal subunits from assembled polysomes that have initiated protein synthesis on an mRNA.

GW(P) bodies

Ribonucleoprotein particles that are thought to be the sites of RNA processing (P bodies) in yeast. The GW RNA-binding protein is a major component of these bodies in mammalian cells, in which they were discovered using an autoantibody. The exact functions of GW(P) bodies remain unclear.

Stress granules

Dynamic pleomorphic structures that are found in the cytoplasm of mammalian cells following physical and chemical perturbations such as oxidative stress. The mRNAs that are present in stress granules are translationally silent.

Lupus

An autoimmune disease in which autoantibodies are generated against normal human proteins, including small nuclear ribonucleoproteins (snRNPs). Autoantibodies can be used to identify RNA-binding proteins and small RNAs contained in snRNPs.

Exosomes

Membrane-bound vesicles that are involved in cell-to-cell exchange of proteins and lipids. Recent evidence indicates that retroviruses use exosomes to augment their infectivity and that mRNAs and microRNAs associate with exosomes for cell-to-cell exchange.

Selfish DNA operons

In bacterial DNA operons, the genes are located in close proximity to each other and this organization increases the probability that they are passaged together during horizontal transfer to other cells. A cell that acquires an entire functioning set of genes is likely to gain an adaptive advantage.

Synexpression

Synchronous temporal or spatial expression of groups of genes during development.

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Keene, J. RNA regulons: coordination of post-transcriptional events. Nat Rev Genet 8, 533–543 (2007). https://doi.org/10.1038/nrg2111

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