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Regulatory roles of natural antisense transcripts

Abstract

Mammalian genomes encode numerous natural antisense transcripts, but the function of these transcripts is not well understood. Functional validation studies indicate that antisense transcripts are not a uniform group of regulatory RNAs but instead belong to multiple categories with some common features. Recent evidence indicates that antisense transcripts are frequently functional and use diverse transcriptional and post-transcriptional gene regulatory mechanisms to carry out a wide variety of biological roles.

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Figure 1: Modulation of transcription.
Figure 2: Induction of chromatin and DNA epigenetic changes by natural antisense transcripts.
Figure 3: Nuclear and cytoplasmic sense–antisense RNA pairing.

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Acknowledgements

We are grateful to M. P. van der Brug, B. H. Miller, J. P. Silva and S. P. Brothers for insightful comments and careful reading of the manuscript. Discussions with Y. Hayashizaki, G. St-Laurent III and other colleagues within the FANTOM Transcriptomics consortium have also been highly valuable to us.

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Correspondence to Claes Wahlestedt.

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FURTHER INFORMATION

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Natural antisense transcripts platform

Glossary

AU-rich element

(ARE). A region in an RNA transcript with frequent A and U nucleotides, such as AUUUA, that targets the RNA for degradation.

Dicer

An RNase III family endonuclease that processes dsRNA and pre-miRNAs into siRNAs and miRNAs, respectively.

ENCODE

(ENCyclopedia Of DNA Elements). A publicly funded project that aims to find functional elements in the human genome.

MicroRNA

(miRNA). Small (20–25 nucleotides) ssRNA that is thought to regulate the expression of other genes, either through inhibiting protein translation or through degrading a target mRNA transcript, by a process that is similar to RNAi.

Piwi-interacting RNA

A small (25–35 nucleotides) RNA species that is processed from precursor ssRNA, independently of Dicer, and forms a complex with the Piwi protein. piRNAs are probably involved in transposon silencing and stem cell function.

RISC

(RNA-induced silencing complex). A multi-protein complex that incorporates one strand of siRNA and uses it to recognize complementary target mRNA for degradation.

RITS

(RNA-induced transcriptional silencing complex). A multi-protein complex — for example, in fission yeast — that incorporates short RNA molecules, such as siRNAs, and triggers downregulation of transcription of a particular gene or genomic region. This is usually accomplished by the modification of histone tails, which target the genomic region for heterochromatin formation.

Small interfering RNAs

(siRNA). Short (21–23 nucleotides) RNA molecule that is processed from a long dsRNA. siRNAs are functional components of the RISC, and they typically target mRNAs by binding perfectly complementary sequences in the mRNA and causing their degradation.

Transcription unit

A group of expressed sequence tags or mRNAs, usually with alternative splice patterns, that share exonic overlap of at least 1 nucleotide and are in the same chromosomal orientation.

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Faghihi, M., Wahlestedt, C. Regulatory roles of natural antisense transcripts. Nat Rev Mol Cell Biol 10, 637–643 (2009). https://doi.org/10.1038/nrm2738

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