Farley Emma K, Olson Katrina M, Zhang Wei, Brandt Alexander J, Rokhsar Daniel S, Levine Michael S
Department of Molecular and Cell Biology, Division of Genetics, Genomics and Development, Center for Integrative Genomics, University of California, Berkeley, CA 94720-3200, USA. Lewis-Sigler Institute for Integrative Genomics, Princeton University, Princeton, NJ 08544, USA.
Department of Medicine, University of California, San Diego, CA 92093-0688, USA.
Science. 2015 Oct 16;350(6258):325-8. doi: 10.1126/science.aac6948.
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.
转录增强子在发育过程中指导基因表达精确的开启和关闭模式。为了探究这种精确性的基础，我们对Otx-a增强子进行了高通量分析，该增强子在海鞘胚胎的神经板中介导对成纤维细胞生长因子（FGF）信号和局部GATA决定因素的反应。我们提供的证据表明，增强子特异性取决于具有降低结合亲和力的次最大识别基序（“次优化”）。天然的GATA和ETS（FGF）结合位点与共有基序存在不完全匹配。完美匹配介导了强大但异位的基因表达模式。天然位点并非以最佳间隔排列，其间距的细微变化会改变增强子活性。增强子的多层次优化产生了特定但微弱的表达模式，我们认为包括某些“超级增强子”在内的弱增强子簇规避了特异性和活性之间的这种权衡。
