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

一条DNA链可以包含几个基因。一个基因的表达可能会影响其相邻基因的表达。我们在正常和疾病生物学的许多情况下看到这种情况发生。确切地了解这是如何发生的，对于理解基因组重排（即当DNA被破坏并修复时，基因被重新定位）和转基因插入（如在基因治疗中，将新的DNA序列插入基因组）的连锁效应以及理解疾病进展非常重要。它还将增加我们对整合到基因组中并处于休眠状态的病毒如何通过附近基因的表达变化重新激活的理解。 在这个提议中，我们解决了这种非自主基因表达是如何发生的。作为例子，我们使用DIRAS 3基因及其邻居GNG 12-AS 1。这两个基因在DNA上彼此面对，并且它们相距相当大的基因组距离，然而GNG 12-AS 1的表达干扰DIRAS 3的表达，结果DIRAS 3的表达降低。这个过程被称为“转录干扰”。我们最近发现，我们可以表观遗传学操纵GNG 12-AS 1表达，而不突变或修改潜在的DNA序列。这为我们提供了测试两种转录干扰模型的方法。第一个模型考虑了两种能够使转录（聚合酶）朝向彼此移动的酶，因为它们不能彼此通过，所以一种或两种酶需要暂停以防止聚合酶碰撞。第二个模型认为一个基因的表达只是阻止了其他基因对聚合酶的可及性。在我们的实验中，我们将考虑到DNA折叠成环状结构的事实，因此两个基因组距离很远的基因实际上可能非常接近，因此当DNA折叠成环状时，更有可能竞争聚合酶。我们还将跟踪这些基因之间的聚合酶的进展，以绘制暂停位置。这项研究的结果将使人们更深入地了解基因组如何发挥自我调节的功能。新兴的基因编辑技术为基因疗法治疗许多疾病提供了前所未有的机会。表观遗传药物已经存在，可以改变基因表达而不改变潜在的DNA序列。表观遗传和基因治疗的机会使得更好地理解非自主基因表达的机制势在必行。我们正在测试的模型对表观遗传和基因疗法有不同的影响，并将使我们能够预测基因组环境将如何对这些疗法作出反应。

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.