How does the expression of one gene affect that of its neighbour?

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A strand of DNA can contain several genes. The expression of one gene may affect the expression of its neighbouring genes. We see this occurring in many circumstances in normal and disease biology. Understanding exactly how this happens is important for appreciating the knock-on effects of genome rearrangements (i.e when DNA is broken and repaired with the result that genes are repositioned) and transgene insertions (as in gene therapy, where a new DNA sequence is inserted into the genome), and hence for understanding disease progression. It will also increase our understanding of how viruses that integrate into the genome and lie dormant can be reactivated through expression changes in nearby genes. In this proposal we address how such non-autonomous gene expression occurs. As examples we are using the DIRAS3 gene and its neighbour GNG12-AS1. These two genes face each other on the DNA and they are a considerable genomic distance apart, yet the expression of GNG12-AS1 interferes with the expression of DIRAS3, with the result that DIRAS3 expression is lowered. This process is known as "transcription interference". We have recently found that we can epigenetically manipulate GNG12-AS1 expression without mutating or modifying the underlying DNA sequence. This provides us with the means to test two models for transcription interference. The first model considers the two enzymes which enable transcription (polymerases) travelling towards one another and because they cannot pass each other, one or both need to pause to prevent a polymerase collision. The second model considers the expression of one gene simply blocking the accessibility of the other gene to polymerases. In our experiments we will take into consideration the fact that DNA is folded into looping structures, so that two genes separated by a big genomic distance may in fact be in close proximity, and thus more likely to compete for polymerase when the DNA is folded into loops. We will also track the progress of polymerases between these genes to map pausing positions. The results of this study will give a deeper understanding of how the genome functions to regulate itself. Emerging technologies for gene editing are providing unprecedented opportunities for gene therapy to treat many diseases. Epigenetic drugs already exist that change gene expression without changing the underlying DNA sequence. The opportunities for epigenetic- and gene therapy make it imperative to better understand the mechanisms of non-autonomous gene expression. The models that we are testing have different implications for epigenetic and gene therapies and will allow us to predict how the genome environment will respond to these therapies.