West Adam G, Fraser Peter
Division of Cancer Sciences and Molecular Pathology, University of Glasgow, Western Infirmary, Glasgow, UK.
Hum Mol Genet. 2005 Apr 15;14 Spec No 1:R101-11. doi: 10.1093/hmg/ddi104.
In this review, we look at the most recent studies of DNA elements that function over long genomic distances to regulate gene transcription and will discuss the mechanisms genes employ to overcome the positive and negative influences of their genomic neighbourhood in order to achieve accurate programmes of expression. Enhancer elements activate high levels of transcription of linked genes from distal locations. Recent technological advances have demonstrated chromatin loop interactions between enhancers and their target promoters. Moreover, there is increasing evidence that these dynamic interactions regulate the repositioning of genes to foci of active transcription within the nucleus. Enhancers have the potential to activate a number of neighbouring genes over a large chromosomal region, hence, their action must be restricted in order to prevent activation of non-target genes. This is achieved by specialized DNA sequences, termed enhancer blockers (or insulators), that interfere with an enhancer's ability to communicate with a target promoter when positioned between the two. Here, we summarize current models of enhancer blocking activity and discuss recent findings of how it can be dynamically regulated. It has become clear that enhancer blocking elements should not be considered only as structural elements on the periphery of gene loci, but as regulatory elements that are crucial to the outcome of gene expression. The transcription potential of a gene can also be susceptible to heterochromatic silencing originating from its chromatin environment. Insulator elements can act as barriers to the spread of heterochromatin. We discuss recent evidence supporting a number of non-exclusive mechanisms of barrier action, which mostly describe the modulation of chromatin structure or modification.
在本综述中，我们审视了关于在基因组上远距离发挥作用以调控基因转录的DNA元件的最新研究，并将讨论基因用以克服其基因组邻域的正负影响从而实现精确表达程序的机制。增强子元件可从远端位置激活相连基因的高水平转录。最近的技术进展已证实增强子与其靶启动子之间存在染色质环相互作用。此外，越来越多的证据表明，这些动态相互作用调控着基因在细胞核内重新定位到活跃转录位点的过程。增强子有可能在大片染色体区域激活多个相邻基因，因此，必须限制其作用以防止非靶基因被激活。这是通过称为增强子阻断剂（或绝缘子）的特殊DNA序列实现的，当它们位于增强子和靶启动子之间时，会干扰增强子与靶启动子通信的能力。在此，我们总结了增强子阻断活性的当前模型，并讨论了其如何被动态调控的最新研究发现。现已明确，增强子阻断元件不应仅被视为基因座周边的结构元件，而应被视为对基因表达结果至关重要的调控元件。基因的转录潜能也可能易受源自其染色质环境的异染色质沉默的影响。绝缘子元件可作为异染色质扩散的屏障。我们讨论了支持多种非排他性屏障作用机制的最新证据，这些机制大多描述了染色质结构或修饰的调节。
