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In vivo enhancer analysis of human conserved non-coding sequences

机译：人体保守非编码序列的体内增强子分析

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Identifying the sequences that direct the spatial and temporal expression of genes and defining their function in vivo remains a significant challenge in the annotation of vertebrate genomes. One major obstacle is the lack of experimentally validated training sets. In this study, we made use of extreme evolutionary sequence conservation as a filter to identify putative gene regulatory elements, and characterized the in vivo enhancer activity of a large group of non-coding elements in the human genome that are conserved in human-pufferfish, Takifugu (Fugu) rubripes, or ultra-conserved(1) in human-mouse-rat. Wetested 167 of these extremely conserved sequences in a transgenic mouse enhancer assay. Here we report that 45% of these sequences functioned reproducibly as tissue-specific enhancers of gene expression at embryonic day 11.5. While directing expression in a broad range of anatomical structures in the embryo, the majority of the 75 enhancers directed expression to various regions of the developing nervous system. We identified sequence signatures enriched in a subset of these elements that targeted forebrain expression, and used these features to rank all 3,100 non-coding elements in the human genome that are conserved between human and Fugu. The testing of the top predictions in transgenic mice resulted in a threefold enrichment for sequences with forebrain enhancer activity. These data dramatically expand the catalogue of human gene enhancers that have been characterized in vivo, and illustrate the utility of such training sets for a variety of biological applications, including decoding the regulatory vocabulary of the human genome.
机译：鉴定指导基因的时空表达的序列并确定其在体内的功能仍然是脊椎动物基因组注释中的重大挑战。一个主要障碍是缺乏经过实验验证的训练集。在这项研究中，我们利用极端进化序列保守性作为过滤器来鉴定推定的基因调控元件，并描述了在河豚鱼中保守的人类基因组中大量非编码元件的体内增强子活性， Takifugu（Fugu）rubripes，或人类-小鼠大鼠中超保守的（1）。在转基因小鼠增强子测定中，我们测试了167个这些高度保守的序列。在这里，我们报告这些序列的45％作为可再生的功能在胚胎第11.5天作为基因表达的组织特异性增强子。在指导胚胎中广泛的解剖结构表达的同时，75种增强剂中的大多数将表达指向发育中的神经系统的各个区域。我们鉴定了富集了这些针对前脑表达的元素的子集的序列签名，并使用这些功能对人类基因组和Fugu之间保守的3,100个非编码元素进行了排名。对转基因小鼠中最高预测值的测试导致具有前脑增强子活性的序列富集了三倍。这些数据极大地扩展了已在体内表征的人类基因增强剂的目录，并说明了此类训练集在多种生物学应用中的用途，包括解码人类基因组的调节词汇。

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