Genomic and Functional Analyses of Conserved Noncoding Regions in Vertebrates

双向启动子被定义为福尔斯两个方向相反的基因之间的基因间空间中的共享调控区，这两个基因之间的间隔不超过1，000 bp。 这些基因以头对头的方式排列，并相互转录。 这样一对基因的转录起始位点（TSS）的紧密排列被认为是基因组中的非随机事件，事实证明，具有这种结构的启动子数量多于预期。 产生双向基因对的一种可能的情况是染色体重组，使两个TSS的末端非常接近。 这种形成可能是不可逆的，因为联合的破坏（在双向启动子内或附近）会中断两个基因的正常调节，深刻影响正常的基因组功能。 我们已经在多个基因组中定位了双向启动子。 在这样做的过程中，我们正在创建多个脊椎动物谱系中启动子序列的第一个高置信度调控图谱。 除了表征启动子区域，我们有兴趣确定新类型的元素，如基因表达的负调控因子（NRE）。 与大量关于正作用元件如增强子和启动子的文献相反，顺式作用NRE尚未被广泛研究。 尽管它们在文献中很少，但这些元素在基因组中可能很丰富。 NRE的实例包括沉默子和增强子阻断（EB）元件，沉默子在其调控下降低基因的表达，增强子阻断（EB）元件在置于两者之间时阻止增强子对启动子的作用，但在其他情况下不阻止。 通过开发一种实验鉴定NRE的策略，我们已经在人类基因组中鉴定出具有这些功能的新元件。 这两个研究项目都研究了顺式作用元件，并集中在转录因子结合位点的鉴定上，转录因子结合位点作为反式作用元件，作为基因调控的基本组成部分。每个项目都公布了监管主题。在我们的工作过程中，新的基序被牵连作为沉默剂和新的生物学见解被揭示为替代启动子的调节。已经建立了一个合作的努力，以确定涉及这些图案和表观遗传事件，控制基因表达在这些途径在癌症的调控网络。

A bidirectional promoter is defined as the shared regulatory region that falls in the intergenic space between two oppositely oriented genes, which are separated by no more than 1,000 bp. These genes are organized in a head-to-head arrangement and transcribed away from one another. The closely spaced arrangement of the transcription start sites (TSSs) for such a pair of genes is recognized as a nonrandom event in the genome, proven by the fact that a greater than expected number of promoters have this architecture. One plausible scenario for the creation of bidirectional gene pairs is chromosomal recombination bringing the ends of two TSSs in close proximity. This formation is likely to be irreversible because breakage of the union (within or near the bidirectional promoter) would interrupt the normal regulation of two genes profoundly affecting normal genomic function. We have mapped bidirectional promoters in multiple genomes. In doing so, we are creating the first high-confidence regulatory map of promoter sequences in multiple vertebrate lineages. In addition to characterizing promoter regions, we are interested in identifying novel types of elements such as negative regulators of gene expression (NREs). In contrast to the large body of literature on positively acting elements such as enhancers and promoters, cis-acting NREs have not been extensively studied. Despite their scarcity in the literature, these elements are likely to be abundant in the genome. Examples of NREs include silencers, which decrease expression of a gene under their regulation and enhancer-blocking (EB) elements, which prevent the action of an enhancer on a promoter when placed between the two, but not otherwise. By developing a strategy to experimentally identify NREs, we have identified novel elements with these functions in the human genome. Both of these research projects examine cis-acting elements and converge on the identification of transcription factor binding sites, which as trans-acting elements, act as the basic components of gene regulation. Regulatory motifs have been published for each of the projects. During the course of our work, novel motifs were implicated as silencers and new biological insights were revealed for the regulation of alternative promoters. A collaborative effort has been established to define the regulatory networks involving these motifs and epigenetic events that control gene expression in these pathways during cancer.