Suboptimization of developmental enhancers.
Suboptimization of developmental enhancers.
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DOI：
10.1126/science.aac6948
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发表时间：
2015-10-16
期刊：
影响因子：
--
通讯作者：
Levine MS
中科院分区：
文献类型：
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作者：
Farley EK;Olson KM;Zhang W;Brandt AJ;Rokhsar DS;Levine MS
转录增强子在发育过程中指导基因表达的精确开-关模式。为了探索这种精确度的基础，我们对Otx-a增强子进行了高通量分析，该增强子介导玻璃海鞘胚胎神经板中响应成纤维细胞生长因子（FGF）信号传导和局部加塔决定子的表达。我们提供的证据表明，增强子的特异性依赖于次最大识别基序具有降低的结合亲和力（“次优化”）。天然加塔和ETS（FGF）结合位点含有与共有基序的不完全匹配。完美匹配介导了基因表达的强大但异位的模式。天然位点没有以最佳间隔排列，并且其间距的细微变化改变增强子活性。多层次的增强子次优化产生特定的，但较弱的表达模式，我们建议弱增强子的集群，包括某些“超级增强子”，规避这种权衡的特异性和活性。
Transcriptional enhancers direct precise on-off patterns of gene expression during development. To explore the basis for this precision, we conducted a high-throughput analysis of the Otx-a enhancer, which mediates expression in the neural plate of Ciona embryos in response to fibroblast growth factor (FGF) signaling and a localized GATA determinant. We provide evidence that enhancer specificity depends on submaximal recognition motifs having reduced binding affinities (“suboptimization”). Native GATA and ETS (FGF) binding sites contain imperfect matches to consensus motifs. Perfect matches mediate robust but ectopic patterns of gene expression. The native sites are not arranged at optimal intervals, and subtle changes in their spacing alter enhancer activity. Multiple tiers of enhancer suboptimization produce specific, but weak, patterns of expression, and we suggest that clusters of weak enhancers, including certain “superenhancers,” circumvent this trade-off in specificity and activity.