DNA interaction networks: an information highway for regulated gene expression in the 3-dimentional space of the nucleus.
DNA interaction networks: an information highway for regulated gene expression in the 3-dimentional space of the nucleus.
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DOI：
10.1038/cr.2009.133
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发表时间：
2009-12
期刊：
影响因子：
44.1
通讯作者：
Fu XD
中科院分区：
文献类型：
--
作者：
Wang D;Fu XD
在这个基因组时代，研究领域已经发生了戏剧性的转变，发现了基于单个基因的传统研究无法接近的新生物学原理，并且由于技术突破，这一过程正在加速，主要是由下一代测序推动的。多年的研究已经建立了关于转录的教条式观点，即基因启动子驱动转录起始，转录起始受到远端增强子的调节[1]。大多数生物化学切割的增强子位于基因启动子附近，很少超出基因边界。这种传统的基因单位观点受到了全基因组定位分析的挑战，近年来，全基因组定位分析揭示了许多DNA结合转录因子与基因组位点的结合可能远离其调控的基因。例如，发现激活的雌激素受体α（ERα）主要结合于人类基因组中的基因间区域，而不是对雌激素刺激有反应的基因启动子附近[2]。这和许多其他类似的研究提出了一个普遍的问题，关于这些结合事件中的一些是偶然的还是功能性的，如果功能性的，这些增强子如何找到它们的靶启动子来赋予信号诱导的基因表达调控。为了避免一个转录单位的转录活动与另一个转录单位的干扰，也存在被CTCF蛋白质束缚的称为绝缘子的DNA元件，其防止增强子影响其多个相邻基因，但对绝缘子如何工作的理解是一个不断发展的过程。绝缘子复合物最初被认为是跟踪增强子上组装的转录复合物到靶基因启动子的路障。虽然这种跟踪模型与研究单个基因单位的许多实验证据一致，但很难想象转录复合物如何能够长途旅行，特别是当跨越一个或多个其他活性转录单位时，到达其最终目的地。因此，提出了DNA成环模型来解释长距离增强子-启动子相互作用，这可能是通过在增强子和启动子上形成的蛋白质复合物的相互作用来实现的[3]。在这方面，绝缘子可能通过增强一些特定的长距离相互作用而发挥作用，同时抑制其他相互作用以促进增强子和启动子之间的特定伙伴关系，这与最近的基因组研究一致[4]。全基因组关联扫描（GWAS）显示，（通常以单核苷酸多态性（SNP）的形式）在遗传上与特定的人类疾病相关联，通常位于基因组中的基因荒漠区域，最新的例子是人类9号染色体上与冠心病相关的基因座[5]。这些发现挑战了基因中心疾病机制的传统智慧，并提出了许多基因沙漠区域可能通过染色体内甚至染色体之间的长距离DNA-DNA相互作用提供关键调控功能的可能性。
In this genomic era, the research landscape has been taking a dramatic turn in discovering new biological principles that have been unapproachable from traditional studies on the basis of individual genes and this process is accelerating because of technological breakthroughs, largely fueled by the next generation sequencing. Many years of research have established a dogmatic view on transcription that gene promoters drive transcriptional initiation, which is subject to modulation by distal enhancers [1]. Most biochemically dissected enhancers are localized in the vicinity of gene promoters and are rarely beyond gene boundaries. This traditional view of gene units is now challenged by genome-wide location analysis in recent years, which reveals that many DNA binding transcription factors bind to genomic loci that can be far away from their regulated genes. For example, the activated estrogen receptor α (ERα) was found to largely bind to intergenic regions in the human genome, rather than near gene promoters responsive to estrogen stimulation [2]. This and many other similar studies raise a general question with respect to whether some of those binding events are fortuitous or functional, and if functional, how these enhancers find their target promoters to confer signalinduced regulation of gene expression. In order to avoid interference of transcriptional activities of one transcription unit with another, there also exist DNA elements called insulators bound by the CTCF protein that prevent enhancers from influencing their multiple neighboring genes, but understanding of how insulators work is an evolving process. The insulator complex was initially thought to serve as a roadblock to tracking of transcription complexes assembled on enhancers to target gene promoters. While this tracking model is consistent with many lines of experimental evidence from studying individual gene units, it is difficult to envision how a transcription complex is able to travel a long distance, especially when across one or multiple other active transcription units, to reach its final destination. The DNA looping model was thus proposed to explain long distance enhancer-promoter interactions, which are likely instrumented by interactions of protein complexes formed on both enhancers and promoters [3]. In this regard, an insulator may function through enhancing some specific longdistance interactions while suppressing others to facilitate specific partnership between enhancers and promoters, which is consistent with recent genomic studies [4].Last, but not least, genome-wide association scanning (GWAS) has revealed that genomic landmarks (often in the form of single nucleotide polymorphisms (SNPs)) genetically linked to specific human diseases are frequently located in gene desert regions in the genome, the latest example being a locus associated with coronary heart disease in human chromosome 9 [5]. These findings challenge the traditional wisdom of gene-central disease mechanisms and raise the possibility that many gene desert regions may provide critical regulatory functions through long-distance DNA-DNA interactions within chromosomes or even between chromosomes.
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