Thorne James L, Campbell Moray J, Turner Bryan M
University of Birmingham Medical School, Edgbaston, Birmingham, B15 2TT, UK.
Int J Biochem Cell Biol. 2009 Jan;41(1):164-75. doi: 10.1016/j.biocel.2008.08.029. Epub 2008 Sep 2.
Transcription factors, chromatin and chromatin-modifying enzymes are key components in a complex network through which the genome interacts with its environment. For many transcription factors, binding motifs are found adjacent to the promoter regions of a large proportion of genes, requiring mechanisms that confer binding specificity in any given cell type. These include association of the factor with other proteins and packaging of DNA, as chromatin, at the binding sequence so as to inhibit or facilitate binding. Recent evidence suggests that specific post-translational modifications of the histones packaging promoter DNA can help guide transcription factors to selected sites. The enzymes that put such modifications in place are dependent on metabolic components (e.g. acetyl CoA, S-adenosyl methionine) and susceptible to inhibition or activation by environmental factors. Local patterns of histone modification can be altered or maintained through direct interaction between the transcription factor and histone modifying enzymes. The functional consequences of transcription factor binding are also dependent on protein modifying enzymes, particularly those that alter lysine methylation at selected residues. Remarkably, the role of these enzymes is not limited to promoter-proximal events, but can be linked to changes in the intranuclear location of target genes. In this review we describe results that begin to define how transcription factors, chromatin and environmental variables interact and how these interactions are subverted in cancer. We focus on the nuclear receptor family of transcription factors, where binding of ligands such as steroid hormones and dietary derived factors provides an extra level of environmental input.
转录因子、染色质及染色质修饰酶是一个复杂网络中的关键组成部分，基因组通过该网络与环境相互作用。对于许多转录因子而言，在很大一部分基因的启动子区域附近可发现结合基序，这就需要在任何特定细胞类型中赋予结合特异性的机制。这些机制包括该因子与其他蛋白质的结合以及DNA作为染色质在结合序列处的包装，从而抑制或促进结合。最近的证据表明，包装启动子DNA的组蛋白的特定翻译后修饰有助于将转录因子引导至选定的位点。进行此类修饰的酶依赖于代谢成分（如乙酰辅酶A、S-腺苷甲硫氨酸），并易受环境因素的抑制或激活。组蛋白修饰的局部模式可通过转录因子与组蛋白修饰酶之间的直接相互作用而改变或维持。转录因子结合的功能后果也取决于蛋白质修饰酶，尤其是那些改变选定残基处赖氨酸甲基化的酶。值得注意的是，这些酶的作用不仅限于启动子近端事件，还可能与靶基因在核内位置的变化有关。在本综述中，我们描述了一些结果，这些结果开始界定转录因子、染色质和环境变量如何相互作用，以及这些相互作用在癌症中是如何被颠覆的。我们重点关注转录因子的核受体家族，其中类固醇激素和饮食衍生因子等配体的结合提供了额外的环境输入水平。
