Trends in Genetics
Transcriptional interference – a crash course
Section snippets
What is transcriptional interference?
In this article, we wish to define transcriptional interference (TI) specifically as the suppressive influence of one transcriptional process, directly and in cis on a second transcriptional process. Our definition of TI (see Glossary) excludes the kind of interference that results from the following: (i) the binding of a repressor to its operator overlapping a promoter [1]; (ii) promoter modification, such as methylation [2]; (iii) hindering the progress of an elongating RNA polymerase (RNAP)
What is the importance of transcriptional interference?
In a genome, interfering promoters can exist naturally either as an integral part of a genetic network or as a reflection of the arrival of a transposable element. Alternatively, they can exist as a result of either an intended experimental manipulation (e.g. in the studies of Proudfoot 11, 12, 13, Eszterhas et al. [14], and Padidam and Cao [15]) or an unintended manipulation (e.g. the insertion of foreign cloned DNA 16, 17, 18). We first turn our attention to the importance of the natural
How widespread is transcriptional interference?
Nasser et al. [35] have suggested that the use of promoter interactions as a mechanism of gene regulation co-evolved with factor-dependent regulation or that there was a primordial RNA-polymerase-dependent homeostatic regulation and an extra level of control by transcription factors has evolved during the course of evolution. Examples of TI as a means of gene regulation are common in the genomes of ‘extrachromosomal’ elements such as bacteriophages 19, 36, 37, 38, transposable elements [39],
How does transcriptional interference work?
Although reports of TI in both prokaryotes and eukaryotes have been published over many years, few studies have addressed the underlying mechanisms. The earlier publications that have influenced our understanding of the mechanisms involved are in vivo studies on convergent promoters by Ward and Murray [61], an in vitro study on promoters arranged both convergently and in-tandem by Horowitz and Platt [62] and, in particular, the in vivo study of a convergent promoter pair by Elledge and Davis
Outlook
Eszterhas et al. [14] set out to obtain some systematic understanding of the mechanisms operating in TI in mouse leukemic cells. They studied the expression of two reporter genes each bounded by a CMV promoter and an SV40 large T antigen polyadenylation signal. They studied all arrangements (convergent, divergent and tandem) in both orientations and integrated them at two different chromosomal loci and concluded that ‘the two transcriptional units interfere with each other in ways that cannot
Concluding remarks
TI occurs in most genomes and has probably persisted during evolution because of its potential use in regulating gene expression. A variety of mechanisms have been identified and successfully studied, at least in simple systems. A major aim for the future is to exploit mathematical modelling to characterize TI, and a major issue to explore further is the fate of an elongating RNAP when it meets a DNA-bound obstacle, either moving or stationary.
Acknowledgements
We wish to acknowledge the help of the other members of the Egan laboratory and of Kim Sneppen (NORDITA) in writing this article. Research in the Egan laboratory was funded by the Australian Research Council and the National Institutes of Health.
Glossary
- Transcriptional interference:
- the suppressive influence of one transcriptional process, directly and in cis, on a second transcriptional process.
- Promoter competition:
- occupation by RNA polymerase (RNAP) of one promoter directly precludes RNA-polymerase binding at a second promoter. This can be extended to include competition between two promoters for the same enhancer.
- Occlusion:
- transcription across a promoter from an external promoter transiently precludes its occupation by RNAP and/or associated
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