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Gene regulation by antisense transcription

Key Points

  • Antisense transcripts are widespread and are found in all kingdoms of life. Their expression can be regulated either coordinately or independently of their neighbouring genes.

  • Antisense transcripts can regulate the expression of their target genes at one or multiple steps of the gene expression process, from transcription and translation to RNA degradation.

  • Antisense transcripts may have a general role in conferring sequence specificity and scaffolding activity on chromatin modifiers.

  • Pairs of sense–antisense transcripts can form self-regulatory circuits in which an equilibrium between sense and antisense expression is reached. This specific organization confers regulatory advantages over transcription factor proteins, which are the best-studied regulators of gene expression. Such organization affects both final expression levels of the sense gene and the dynamics of the regulatory response.

  • Gene regulation mediated by antisense transcription provides efficient repression of gene expression in an 'off' state and increases both gene expression responsiveness and cell-to-cell variability when induced.

  • Antisense transcripts provide an efficient mode of regulation with rapid response and with rapid recovery upon removal of the stimulus, which allows cells to quickly change between distinct states.

  • Antisense expression can coordinate gene expression either in cis or in trans. Their ability to interact with other regulatory mechanisms emphasizes their different but complementary role compared with gene regulators such as transcription factors, which have been more widely studied.

  • The ability of antisense transcripts to integrate diverse types of regulatory signals and to function at multiple steps of the gene expression process makes them hubs for gene regulation.

  • Antisense transcripts show low (but non-negligible) evolutionary conservation, which suggests that their fast generation is a mechanism to adapt to new conditions and, consequently, potentially increases the fitness of the species.

Abstract

Antisense transcription, which was initially considered by many as transcriptional noise, is increasingly being recognized as an important regulator of gene expression. It is widespread among all kingdoms of life and has been shown to influence — either through the act of transcription or through the non-coding RNA that is produced — almost all stages of gene expression, from transcription and translation to RNA degradation. Antisense transcription can function as a fast evolving regulatory switch and a modular scaffold for protein complexes, and it can 'rewire' regulatory networks. The genomic arrangement of antisense RNAs opposite sense genes indicates that they might be part of self-regulatory circuits that allow genes to regulate their own expression.

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Figure 1: Effects of antisense expression on transcription initiation.
Figure 2: Co-transcriptional effects of antisense transcription.
Figure 3: Post-transcriptional effects of antisense transcription.
Figure 4: Biological implications of antisense expression.

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Acknowledgements

The authors thank R. Aiyar, A.I. Järvelin, J. Zaugg, W. Wei and the members of the Steinmetz laboratory for their discussions and critical comments on the manuscript. L.M.S acknowledges support by the Deutsche Forschungsgemeinschaft and the US National Institutes of Health.

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Correspondence to Lars M. Steinmetz.

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Glossary

Transcriptional noise

Random fluctuations that are intrinsic to the gene expression process and that cause differences in the levels of specific RNAs among cells in a clonal population.

Cryptic promoters

Weak promoters, the use of which is associated with disruption of chromatin structure. Transcripts produced from such promoters often have unknown functions.

Head-to-head

Pertaining to two transcripts that are divergently oriented and have overlapping 5′ regions.

Tail-to-tail

Pertaining to two transcripts that are convergently oriented and have overlapping 3′ regions.

CpG islands

Genomic regions that contain a high frequency of CG dinucleotides; they are often associated with mammalian promoters and are targets of cytosine methylation.

Gene imprinting

An epigenetic process by which the expression of each allele of a gene depends on its parent of origin; for example, on whether it is the paternal or maternal allele.

Nascent transcript

An RNA molecule that results from ongoing transcription and that is still associated with DNA through the RNA polymerase.

Polymerase pausing

A process in which an RNA polymerase temporarily halts elongation while remaining associated with DNA. It is associated with transcriptional regulation after initiation and is particularly frequent in metazoans.

miRNA sponges

RNA molecules that have multiple binding sites for specific microRNAs (miRNAs); they are therefore able to function as decoys to sequester miRNAs and prevent them from binding to their targets.

Dynamic range

The range of expression levels between the minimum expression level of a gene in its basal or repressed state and its maximum expression level upon full activation.

Transcriptional bursting

A stochastic process in which a promoter changes from an inactive state to an active or open state that allows the production of multiple RNAs in a short period of time, before returning to the inactive state.

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Pelechano, V., Steinmetz, L. Gene regulation by antisense transcription. Nat Rev Genet 14, 880–893 (2013). https://doi.org/10.1038/nrg3594

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