Genome-scale functional characterization of Drosophila developmental enhancers in vivo
Genome-scale functional characterization of Drosophila developmental enhancers in vivo
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DOI：
10.1038/nature13395
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发表时间：
2014-08-07
期刊：
影响因子：
64.8
通讯作者：
Stark, Alexander
中科院分区：
文献类型：
--
作者：
Kvon, Evgeny Z.;Kazmar, Tomas;Stark, Alexander
转录增强子是基因表达和动物发育的重要调节因子(1)，其基因组组织、时空活性和序列特性的表征是现代生物学的一个关键目标(2-8)。在这里，我们描述了 7,705 个果蝇增强子候选物的体内活性，覆盖整个胚胎发生过程中非编码非重复基因组的 13.5%。 3,557 (46%) 候选者处于活跃状态，表明全基因组具有 50,000 至 100,000 个发育增强子的高密度。绝大多数增强子表现出在发育过程中高度动态的特定空间模式。大多数似乎调节其邻近基因，这表明顺式调节基因组局部组织成结构域，这些结构域受到染色体结构域、绝缘体结合和基因组进化的支持。然而，12％至21％的增强子似乎会跳过非表达的邻居并调节更远端的基因。最后，我们通过计算确定了增强子活性的预测性和必需的顺式调控基序，并通过实验进行了验证。这项工作提供了对动物调控基因组的组织和增强子序列的组成的全面见解，并证实和概括了先前研究的原理(1,9)。所有增强子模式均使用受控词汇进行手动注释，所有结果均可通过网络界面 (http://enhancers.starklab.org) 获得，包括所有显微镜载玻片的原始图像，用于在任意缩放级别进行手动检查。
Transcriptional enhancers are crucial regulators of gene expression and animal development(1) and the characterization of their genomic organization, spatiotemporal activities and sequence properties is a key goal in modern biology(2-8). Here we characterize the in vivo activity of 7,705 Drosophila melanogaster enhancer candidates covering 13.5% of the non-coding non-repetitive genome throughout embryogenesis. 3,557 (46%) candidates are active, suggesting a high density with 50,000 to 100,000 developmental enhancers genome-wide. The vast majority of enhancers display specific spatial patterns that are highly dynamic during development. Most appear to regulate their neighbouring genes, suggesting that the cis-regulatory genome is organized locally into domains, which are supported by chromosomal domains, insulator binding and genome evolution. However, 12 to 21 per cent of enhancers appear to skip non-expressed neighbours and regulate a more distal gene. Finally, we computationally identify cis-regulatory motifs that are predictive and required for enhancer activity, as we validate experimentally. This work provides global insights into the organization of an animal regulatory genome and the make-up of enhancer sequences and confirms and generalizes principles from previous studies(1,9). All enhancer patterns are annotated manually with a controlled vocabulary and all results are available through a web interface (http://enhancers.starklab.org), including the raw images of all microscopy slides for manual inspection at arbitrary zoom levels.