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Targeting long non-coding RNA to therapeutically upregulate gene expression

A Corrigendum to this article was published on 29 November 2013

This article has been updated

Key Points

  • The human genome is pervasively transcribed. Most RNA transcripts represent non-coding RNAs (ncRNAs), of which there are many categories. This article focuses on long non-coding RNAs (lncRNAs).

  • Many lncRNAs have been shown to be functional and/or related to several human diseases, including various forms of cancer and inheritable diseases such as Huntington's disease and Fragile X syndrome. lncRNAs can positively or negatively regulate gene expression and chromatin architecture.

  • Natural antisense transcripts (NATs) are highly abundant in the human genome and found in many known gene loci where they are transcribed in the opposite direction of conventional protein-coding genes.

  • NATs frequently regulate the expression of protein-coding genes, either positively or negatively. Most NATs mediate transcriptional repression at the chromatin level.

  • AntagoNATs are oligonucleotides that specifically target NATs and are capable of upregulating the expression of corresponding protein coding genes in vitro as well as in vivo.

  • AntagoNATs induce gene upregulation in a gene-locus-specific and reversible manner.

  • AntagoNAT upregulation technology has been applied to the upregulation of genes including growth factors, tumour suppressors, transcription factors and those genes that are deficient in genetic diseases.

  • There is a scarcity of other methods for inducing locus-specific and reversible gene upregulation.

Abstract

The majority of currently available drugs and tool compounds exhibit an inhibitory mechanism of action and there is a relative lack of pharmaceutical agents that are capable of increasing the activity of effectors or pathways for therapeutic benefit. Indeed, the upregulation of many genes, including tumour suppressors, growth factors, transcription factors and genes that are deficient in various genetic diseases, would be desired in specific situations. Recently, key roles for regulatory long non-coding RNAs (lncRNAs) in the regulation of gene expression have begun to emerge. lncRNAs can positively or negatively regulate gene expression and chromatin architecture. Here, we review the current understanding of the mechanisms of action of lncRNAs and their roles in disease, focusing on recent work in the design of inhibitors of the natural antisense transcript (NAT) class of lncRNAs, known as antagoNAT oligonucleotides, and the issues associated with their potential therapeutic application.

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Figure 1: 'Central dogma' in the context of regulatory non-coding RNAs.
Figure 2: Modulation of gene expression by long non-coding RNAs.
Figure 3: Simplified scheme of antagoNAT design.

Change history

  • 29 November 2013

    The second paragraph in the section titled "Challenges in targeting long non-coding RNAs" on page 442 of this Review was inserted during manuscript revision. The wording of this paragraph drew heavily on, and mostly repeated, a paragraph in an earlier review article by J. T. Lee (Lee, J. T. Epigenetic regulation by long noncoding RNAs. Science 338, 1435–1439; 2012). Although the Science review was cited elsewhere in this article, it should also have been cited at this point in order to attribute correctly the ideas expressed by Lee. The author apologizes for introducing this passage, and for the lack of citation to the paper from which it derived, and is pleased to correct the record accordingly.

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Acknowledgements

The author apologizes to colleagues whose work could not be discussed or cited owing to space limitations. He also thanks many members of his laboratory, in particular V. Peschansky and P. Halley, for their critical review of the literature and for providing important help with the manuscript. M. Magistri and Z. Zeier have provided scientific input and expert help in designing the figures. M. A. Faghihi, P. Kapranov and G. St Laurent are acknowledged for their critical reading and/or for providing important input on RNA classification. Finally, the author thanks J. Hsiao, O. Khorkova, C. Coito, P. Frost and others at OPKO-CURNA for helpful discussions.

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Correspondence to Claes Wahlestedt.

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Claes Wahlestedt is a consultant for Opko Health.

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Glossary

MicroRNAs

(miRNAs). Small non-coding RNAs that affect the stability of many mRNAs.

Long non-coding RNAs

(lncRNAs). RNA transcripts greater than 200 nucleotides in length that lack an open reading frame and therefore do not encode protein.

Natural antisense transcript

(NAT). An RNA transcript originating from the opposite strand of a sense (often protein-coding) RNA transcript.

INK4B–ARF–INK4A locus

A locus that encodes three tumour suppressor proteins: INK4B, which is encoded by cyclin-dependent kinase inhibitor 2B (CDKN2B); and INK4A and ARF, which are encoded by CDKN2A.

AntagoNATs

Oligonucleotide inhibitors targeted to a natural antisense transcript (NAT).

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Wahlestedt, C. Targeting long non-coding RNA to therapeutically upregulate gene expression. Nat Rev Drug Discov 12, 433–446 (2013). https://doi.org/10.1038/nrd4018

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