National Center for Bioinformatics, Program of Comparative and Evolutionary Genomics, Faculty of Biological Sciences, Quaid-i-Azam University, Islamabad 45320, Pakistan.
BMC Genomics. 2013 Feb 23;14:122. doi: 10.1186/1471-2164-14-122.
Human genome is enriched with thousands of conserved non-coding elements (CNEs). Recently, a medium throughput strategy was employed to analyze the ability of human CNEs to drive tissue specific expression during mouse embryogenesis. These data led to the establishment of publicly available genome wide catalog of functionally defined human enhancers. Scattering of enhancers over larger regions in vertebrate genomes seriously impede attempts to pinpoint their precise target genes. Such associations are prerequisite to explore the significance of this in vivo characterized catalog of human enhancers in development, disease and evolution.
This study is an attempt to systematically identify the target gene-bodies for functionally defined human CNE-enhancers. For the purpose we adopted the orthology/paralogy mapping approach and compared the CNE induced reporter expression with reported endogenous expression pattern of neighboring genes. This procedure pinpointed specific target gene-bodies for the total of 192 human CNE-enhancers. This enables us to gauge the maximum genomic search space for enhancer hunting: 4 Mb of genomic sequence around the gene of interest (2 Mb on either side). Furthermore, we used human-rodent comparison for a set of 159 orthologous enhancer pairs to infer that the central nervous system (CNS) specific gene expression is closely associated with the cooperative interaction among at least eight distinct transcription factors: SOX5, HFH, SOX17, HNF3β, c-FOS, Tal1beta-E47S, MEF and FREAC.
In conclusion, the systematic wiring of cis-acting sites and their target gene bodies is an important step to unravel the role of in vivo characterized catalog of human enhancers in development, physiology and medicine.
人类基因组富含数千个保守的非编码元件（CNEs）。最近，采用了一种中等通量的策略来分析人类 CNE 在小鼠胚胎发生过程中驱动组织特异性表达的能力。这些数据导致了可公开获得的全基因组功能定义人类增强子目录的建立。增强子在脊椎动物基因组中较大区域的分散严重阻碍了精确定位其精确靶基因的尝试。这种关联是探索该体内鉴定的人类增强子目录在发育、疾病和进化中的意义的前提。
本研究旨在系统地鉴定功能定义的人类 CNE 增强子的靶基因。为此，我们采用了同源/旁系同源映射方法，并将 CNE 诱导的报告基因表达与邻近基因的报道内源性表达模式进行了比较。这一过程为总共 192 个人类 CNE 增强子确定了特定的靶基因。这使我们能够评估增强子搜索的最大基因组搜索空间：感兴趣基因周围的基因组序列为 4 Mb（两侧各 2 Mb）。此外，我们使用人类-啮齿动物比较对 159 对同源增强子对进行了研究，推断中枢神经系统（CNS）特异性基因表达与至少八个不同转录因子的合作相互作用密切相关：SOX5、HFH、SOX17、HNF3β、c-FOS、Tal1beta-E47S、MEF 和 FREAC。
总之，顺式作用位点及其靶基因的系统布线是揭示体内鉴定的人类增强子在发育、生理学和医学中的作用的重要步骤。
