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首页> 外文期刊>Philosophical Transactions of the Royal Society of London, Series B. Biological Sciences >Low-affinity transcription factor binding sites shape morphogen responses and enhancer evolution
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Low-affinity transcription factor binding sites shape morphogen responses and enhancer evolution

机译：低亲和力转录因子结合位点塑造形态发生子反应和增强子进化

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摘要

In the era of functional genomics, the role of transcription factor (TF)–DNA binding affinity is of increasing interest: for example, it has recently been proposed that low-affinity genomic binding events, though frequent, are functionally irrelevant. Here, we investigate the role of binding site affinity in the transcriptional interpretation of Hedgehog (Hh) morphogen gradients. We noted that enhancers of several Hh-responsive Drosophila genes have low predicted affinity for Ci, the Gli family TF that transduces Hh signalling in the fly. Contrary to our initial hypothesis, improving the affinity of Ci/Gli sites in enhancers of dpp, wingless and stripe, by transplanting optimal sites from the patched gene, did not result in ectopic responses to Hh signalling. Instead, we found that these enhancers require low-affinity binding sites for normal activation in regions of relatively low signalling. When Ci/Gli sites in these enhancers were altered to improve their binding affinity, we observed patterning defects in the transcriptional response that are consistent with a switch from Ci-mediated activation to Ci-mediated repression. Synthetic transgenic reporters containing isolated Ci/Gli sites confirmed this finding in imaginal discs. We propose that the requirement for gene activation by Ci in the regions of low-to-moderate Hh signalling results in evolutionary pressure favouring weak binding sites in enhancers of certain Hh target genes.
机译：在功能基因组学时代，转录因子（TF）-DNA结合亲和力的作用日益引起人们的关注：例如，最近有人提出，低亲和力基因组结合事件尽管很常见，但在功能上却无关紧要。在这里，我们调查的刺猬（Hh）形态发生因子梯度的转录解释中的结合位点亲和力的作用。我们注意到，几个Hh响应果蝇基因的增强子对Ci的预测亲和力较低，Ci是在飞行中转导Hh信号的Gli家族TF。与我们最初的假设相反，通过从修补的基因中移植最佳位点来改善dpp，无翅和条带增强子中Ci / Gli位点的亲和力，不会导致对Hh信号的异位反应。相反，我们发现这些增强子需要较低亲和力的结合位点才能在相对较低的信号传导区域正常激活。当这些增强子中的Ci / Gli位点被改变以提高它们的结合亲和力时，我们观察到转录反应中的模式缺陷，与从Ci介导的激活向Ci介导的阻抑的转换一致。包含孤立的Ci / Gli位点的合成转基因报告基因证实了在假想盘中的这一发现。我们提出，在低至中度Hh信号区域中由Ci激活基因的要求导致进化压力有利于某些Hh目标基因的增强子中的弱结合位点。

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