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The antisense of cis and trans: Lost in transcription

Andreas Werner   (29 March 2006)  University of Newcastle upon Tyne

Natural antisense transcripts (NATs) have a mysterious touch; large in numbers with an enigmatic role in gene regulation (9). Imprinted genes and the X chromosome use antisense transcripts to silence the cognate sense transcript (and/or additional proximal genes)(6). This happens in a confined area on only one allele; thus the description “cis-acting” antisense transcripts. Recent advances in bioinformatics have now identified transcripts that show extended regions of overlap but are transcribed from different genomic loci. The obvious name for these RNAs is “trans” NATs (5). Such nomenclature that implies a local mode of action (cis) as compared to a distant impact (trans) in the context of bi-directional transcription is misleading. The two alleles of a gene in a (diploid) eukaryotic cell usually do not co-localize (1). The impact of a mechanism strictly acting in cis would therefore be restricted to one single allele. Such a situation does indeed apply for imprinted genes where the expression of antisense transcripts leads to the silencing of the cognate sense transcript on the same allele without affecting the expression of the sense RNA from the other allele. In the Igf2r/Air imprinted cluster, arguably the best studied example, imprinted expression of the Igf2 receptor is dependent on the expression of the antisense transcript Air. Premature termination of the antisense transcript leads to bi-allelic expression of the Igf2 receptor (8). The “snag” here, is that a sense-antisense overlap between Air and the Igf2r transcript seems to be optional (7).

The majority of so called “cis” NATs are not expressed from a single allele; there is even evidence that bi-allelic expression is required for biological function of sense-antisense pairs (2, 3). In addition, hybrid formation must occur for at least some sense/antisense regulatory mechanisms (4). Because the two alleles of a gene do not co-localize in the cell nucleus there seems to be an element of travelling involved even in cis NATs action. This implies that such NATs meet certain criteria regarding the kinetics of transcription and processing as well as RNA stability and transport. The same requirements, however, hold for so-called “trans” NATs. The fact that cis NATs fall into two groups, one of which very similar to trans NATs makes the cis-trans nomenclature confusing in the context of antisense transcription.

“Noncoding RNAs” for antisense transcripts that function without sense-antisense overlap and NATs for the rest (without distinguishing between cis and trans) may prove to be a more appropriated description.

References

1. Chakalova L, Debrand E, Mitchell JA, Osborne CS, and Fraser P. Replication and transcription: shaping the landscape of the genome. Nat Rev Genet 6: 669-677, 2005.

2. Chen J, Sun M, Kent WJ, Huang X, Xie H, Wang W, Zhou G, Shi RZ, and Rowley JD. Over 20% of human transcripts might form sense-antisense pairs. Nucleic Acids Res 32: 4812-4820, 2004.

3. Kiyosawa H, Yamanaka I, Osato N, Kondo S, and Hayashizaki Y. Antisense transcripts with FANTOM2 clone set and their implications for gene regulation. Genome Res 13: 1324-1334, 2003.

4. Lavorgna G, Dahary D, Lehner B, Sorek R, Sanderson CM, and Casari G. In search of antisense. Trends Biochem Sci 29: 88-94, 2004.

5. Li YY, Qin L, Guo ZM, Liu L, Xu H, Hao P, Su J, Shi Y, He WZ, and Li YX. In silico discovery of human natural antisense transcripts. BMC Bioinformatics 7: 18, 2006.

6. Ogawa Y and Lee JT. Antisense regulation in X inactivation and autosomal imprinting. Cytogenet Genome Res 99: 59-65, 2002.

7. Sleutels F, Tjon G, Ludwig T, and Barlow DP. Imprinted silencing of Slc22a2 and Slc22a3 does not need transcriptional overlap between Igf2r and Air. Embo J 22: 3696-3704, 2003.

8. Sleutels F, Zwart R, and Barlow DP. The non-coding Air RNA is required for silencing autosomal imprinted genes. Nature 415: 810-813, 2002.

9. Werner A and Berdal A. Natural antisense transcripts: sound or silence? Physiol Genomics 23: 125-131, 2005.

Competing interests

None declared

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