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Antisense transcription influences sense transcription

Figure 1: Antisense transcription affects the rate of transcription initiation and nuclear processing of RNA through histone acetylation levels

Figure 1: Antisense transcription affects the rate of transcription initiation and nuclear processing of RNA through histone acetylation levels (Click to Enlarge)

New research by the Mellor and Angel groups, published in Molecular Systems Biology, provides new insights into the biological function of antisense transcription. The results highlight a role of antisense transcription in influencing the production of sense transcripts, ultimately determining the levels of functional protein.

Many genes exhibit antisense transcription, the reading of a gene in the reverse orientation. Although antisense transcription is widespread across eukaryotic genomes, its significance remains elusive. Is it simply a by‐product of gene transcription, or are there biological consequences. Now, a combination of single-cell experiments , mathematical modelling and bioinformatic analysis were employed to address these questions. The research shows that antisense transcription can influence sense transcription by altering the chromatin environment in the vicinity of the sense promoter. These effects are conserved between yeast and humans, despite large differences in gene size.

To determine how antisense transcription influences the production of the sense mRNA and thus gene expression, single molecule RNA FISH at genes with or without antisense trancription was coupled with stochastic modelling of transcription and RNA dynamics. The analysis revealed that high levels of antisense transcription, reduces the rate of sense transcript production and processing, while increasing transcript stability. This ultimately determines the levels of functional protein in the cell. The effects of antisense transcription on sense transcriptioncan be recapitulated simply by increasing levels of histone acetylation in the absence of antisense transcription, by ablating the activity of the Set3 histone deacetylase. The presence of antisense transcription buffers the activity of Set3 to maintain high acetylation.

In summary, quantitative RNA-FISH experiments in combination with a stochastic model of transcription reveal that antisense transcription disrupts the activity of the Set3 lysine deacetylase, thus altering the rates of sense transcript production, processing and stability. This work reveals the conserved functional role of antisense transcription and nicely illustrates the new approaches which are required to unpick the complexities of transcription regulation and gene expression more generally.

Reference

  1. Brown, T, Howe FS, Murray SC, Wouters M, Lorenz P, Seward E, Rata S, Angel A, Mellor J. Antisense Transcription-Dependent Chromatin Signature Modulates Sense Transcript Dynamics. Molecular Systems Biology, 14 (2018), 1-21 doi.org/10.15252/msb.20178007

Work in the Mellor and Angel labs is funded by The Wellcome Trust, The Leverhulme Trust, The Royal Society, BBSRC, EPSRC and EpiGeneSys.

 

 

 

 

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