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Natural antisense transcripts as versatile regulators of gene expression

Nature Reviews Genetics (2024)Cite this article

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Abstract

Long non-coding RNAs (lncRNAs) are emerging as a major class of gene products that have central roles in cell and developmental biology. Natural antisense transcripts (NATs) are an important subset of lncRNAs that are expressed from the opposite strand of protein-coding and non-coding genes and are a genome-wide phenomenon in both eukaryotes and prokaryotes. In eukaryotes, a myriad of NATs participate in regulatory pathways that affect expression of their cognate sense genes. Recent developments in the study of NATs and lncRNAs and large-scale sequencing and bioinformatics projects suggest that whether NATs regulate expression, splicing, stability or translation of the sense transcript is influenced by the pattern and degrees of overlap between the sense–antisense pair. Moreover, epigenetic gene regulatory mechanisms prevail in somatic cells whereas mechanisms dependent on the formation of double-stranded RNA intermediates are prevalent in germ cells. The modulating effects of NATs on sense transcript expression make NATs rational targets for therapeutic interventions.

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Fig. 1: Genomic architecture of bidirectionally transcribed genes.
Fig. 2: NAT-mediated gene regulation through transcriptional interference and DNA–RNA triplex formation.
Fig. 3: Co-transcriptional regulation by NATs.
Fig. 4: NATs regulate mRNA stability and can affect translation.
Fig. 5: Genome-wide effect of NATs in testis.

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Acknowledgements

A.W. receives support from the Northern Counties Kidney Research Fund (18.011) and the Newcastle upon Tyne Hospitals NHS Trust (NU-005589). J.S.M. is supported by SHARP Professorship grant RG193211 from the University of New South Wales Sydney. Related work in the Wahlestedt laboratory was supported in part by National Institutes of Health grants AA29924 and AG079373 and the State of Florida grant 23A17.

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  1. Newcastle University, Newcastle, UK

    Andreas Werner

  2. University of Liverpool, Liverpool, UK

    Aditi Kanhere

  3. University of Miami Miller School of Medicine, Miami, FL, USA

    Claes Wahlestedt

  4. University of New South Wales, Sydney, New South Wales, Australia

    John S. Mattick

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Werner, A., Kanhere, A., Wahlestedt, C. et al. Natural antisense transcripts as versatile regulators of gene expression. Nat Rev Genet (2024). https://doi.org/10.1038/s41576-024-00723-z

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