Key Points
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Traditionally, the different stages of gene expression were considered to be separate processes that operated independently. Biochemical and genetic studies have instead revealed high levels of coupling between the different stages. In recent years, genome-wide and systems-level analyses have greatly extended our understanding of coupling in gene expression, by both revealing the effect that certain forms of coupling have on a more global scale, and unveiling novel forms of coupling that had not been identified using more traditional techniques.
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Genomic analyses of the binding of transcription factors and chromatin remodellers with DNA have revealed extensive coordination and coupling between these factors, forming regulatory networks that control how many genes are expressed.
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Genome-wide analysis of associations between the nuclear pore and nuclear lamina revealed extensive coupling between the transcription level of a given gene and its nuclear localization. In particular, different subcomplexes within the nuclear pore associate with specific types of genetic loci.
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Genomic analyses of mRNA processing have shown that splicing commitment occurs co-transcriptionally, but that in yeast the splicing completes post-transcriptionally, and that the spliceosome can regulate expression of specific types of mRNAs by increasing or decreasing their splicing efficiencies.
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Microarray analyses have also shown that the co-transcriptional recruitment of mRNA export factors results in functional specificities, in which different factors transport specific types of mRNAs; the combination of whole-genome screens and array analyses also demonstrated an important role for the exosome in mRNA export.
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Chromatin immunoprecipitation coupled with microarray (ChIP–chip) analyses in higher eukaryotes provide support for a dynamic messenger ribonucleoprotein (mRNP) model, in which the composition of the mRNP associated with the nascent transcript changes along the length of the transcript.
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Whole-genome analysis of the associations between proteasomal components and chromatin revealed a widespread role for the proteasome in transcriptional activation and enrichment of binding of the proteasome at ribosomal protein genes. This coupling between the protein synthesis and degradation machineries could allow feedback that globally reduces expression levels when the proteasome is compromised.
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Network analysis of the genomic associations of many factors involved in gene expression revealed novel connections between the different levels of gene expression. In particular, factors involved in nuclear transport, general transcription factors, RNA-processing factors and nucleosome remodellers were found to exhibit highly similar binding profiles and to have a large number of neighbours, allowing them to exert global influences on many genes at once.
Abstract
Genome-scale analyses have allowed us to progress beyond studying gene expression at the level of individual components of a given process by providing global information about functional connections between genes, mRNAs and their regulatory proteins. Such analyses have greatly increased our understanding of the interplay between different events in gene regulation and have highlighted previously unappreciated functional connections, including coupling between nuclear and cytoplasmic processes. Genome-wide approaches have also revealed extensive coordination within regulatory levels, such as the organization of transcription factors into regulatory motifs. Overall, these studies enhance our understanding of how the many components of the eukaryotic cell function as a system to allow both coordination and versatility in gene expression.
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Acknowledgements
The authors would like to thank D. Muzzey, M. Moore, I. Swinburne and C. Brown for helpful discussions and critical evaluation of the manuscript, and the support of grants from the US National Institutes of Health.
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Glossary
- Histone variants
-
Histone variants share amino-acid sequence homology and core structural similarity with the canonical histone proteins but are functionally distinct. Some variants are restricted to certain regions of the chromosome, such as the centromere-specific H3-like variant CenpA. Others are used only during specialized processes, such as the histone H2A variant H2A.X, which binds to DNA with double-strand breaks and marks the region undergoing DNA repair.
- Nuclear pore
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The nuclear pore is a large protein complex that traverses the nuclear envelope, allowing transport between the nucleus and cytoplasm. The proteins that form the nuclear pore are known as nucleoporins.
- Dosage compensation complex
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The dosage compensation complex is an RNA–protein complex in Drosophila melanogaster that mediates the twofold hypertranscription of genes from the X chromosome in males, resulting in equalized levels of X-chromosome products in both sexes.
- Synthetic genetic interaction
-
A synthetic genetic interaction occurs when the severity of the phenotype caused by the absence of two genes is more or less than the sum of the phenotypes of the individual gene knockouts. Two genes that are non-essential when deleted individually but for which the deletion of both is fatal are termed synthetic lethal.
- Mutual information
-
Mutual information is a measure of dependence between two variables. If one variable is highly predictive of the other, then the mutual information between the two will be high. Importantly, this does not imply that the two variables exhibit the same behaviour, for anti-correlated variables are still co-dependent and thus have high mutual information.
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Komili, S., Silver, P. Coupling and coordination in gene expression processes: a systems biology view. Nat Rev Genet 9, 38–48 (2008). https://doi.org/10.1038/nrg2223
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DOI: https://doi.org/10.1038/nrg2223
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