In search of antisense

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Abstract

In recent years, natural antisense transcripts (NATs) have been implicated in many aspects of eukaryotic gene expression including genomic imprinting, RNA interference, translational regulation, alternative splicing, X-inactivation and RNA editing. Moreover, there is growing evidence to suggest that antisense transcription might have a key role in a range of human diseases. Consequently, there have been several recent attempts to identify novel NATs. To date, ∼2500 mammalian NATs have been found, indicating that antisense transcription might be a common mechanism of regulating gene expression in human cells. There are increasingly diverse ways in which antisense transcription can regulate gene expression and evidence for the involvement of NATs in human disease is emerging. A range of bioinformatic resources could be used to assist future antisense research.

Section snippets

Functions of antisense transcripts

Although recent studies have identified many NATs, our understanding of how antisense transcription regulates gene expression in human cells remains largely incomplete. However, pioneering studies in several eukaryotic systems have identified three general mechanisms by which antisense transcription can regulate gene expression: transcriptional interference, rna masking and double-stranded rna (dsRNA)-dependent mechanisms (Figure 1).

Relevance of antisense transcription to disease

Given the diverse ways in which NATs can affect the expression of eukaryotic genes, it is hardly surprising that changes in antisense transcription can lead to abnormal patterns of gene expression, which in turn contribute to pathological phenotypes. To date, there are only a few examples of antisense transcripts that are implicated in human disease. However, it is likely that these examples are only the tip of a rather large iceberg.

For several years it has been clear that many imprinted genes

Web resources for in-silico detection of antisense transcription

The availability of the complete human genome sequence and the accumulation of millions of expressed sequences (mRNAs and ESTs) have made it possible for large-scale predictions of naturally occurring antisense transcription. Indeed, in the past two years, several studies have used these sources of information in attempts to produce comprehensive datasets of sense–antisense pairs. The results of these studies are summarized in Table 1.

The first study, conducted by Lehner et al. [1], took the

Concluding remarks

A major challenge for the future will be to establish which of the identified human NATs actually affect gene expression and by which mechanism. Ideally, these questions should be addressed in parallel for many NATs. The mechanisms discussed in this review make predictions that are amenable to large-scale parallel analysis. For example, RNAi mechanisms would produce endogenous 21–23-nt RNAs derived from the regions of overlapping transcription, and these could be identified using cloning

Acknowledgements

We thank Gisela Storz, Doug Higgs and Galit Rotman for helpful comments and suggestions.

Glossary

Glossary

Cis and trans-NATs:
natural antisense transcripts (NATs) are RNAs that contain sequence that is complementary to other endogenous RNAs. They might be transcribed in cis from opposing DNA strands at the same genomic locus or in trans from separate loci.
double-stranded RNAs (dsRNAs):
this variable-size RNA form, deriving from the interaction of antisense partners, can affect gene expression via RNA editing or RNA interference mechanisms.
microRNAs (miRNAs):
these very small, trans-acting RNA

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