Department of Developmental Biology and Cell Networks - Cluster of Excellence, Heidelberg University, Centre for Organismal Studies (COS) Heidelberg, Heidelberg, Germany.
Institut de Genomique Fonctionnelle de Lyon, Univ Lyon, CNRS UMR 5242, Ecole Normale Superieure de Lyon, Universite Claude Bernard Lyon 1, Lyon, France.
Nat Commun. 2022 Aug 26;13(1):5037. doi: 10.1038/s41467-022-32408-8.
Hox proteins have similar binding specificities in vitro, yet they control different morphologies in vivo. This paradox has been partially solved with the identification of Hox low-affinity binding sites. However, anterior Hox proteins are more promiscuous than posterior Hox proteins, raising the question how anterior Hox proteins achieve specificity. We use the AP2x enhancer, which is activated in the maxillary head segment by the Hox TF Deformed (Dfd). This enhancer lacks canonical Dfd-Exd sites but contains several predicted low-affinity sites. Unexpectedly, these sites are strongly bound by Dfd-Exd complexes and their conversion into optimal Dfd-Exd sites results only in a modest increase in binding strength. These small variations in affinity change the sensitivity of the enhancer to different Dfd levels, resulting in perturbed AP-2 expression and maxillary morphogenesis. Thus, Hox-regulated morphogenesis seems to result from the co-evolution of Hox binding affinity and Hox dosage for precise target gene regulation.
Hox 蛋白在体外具有相似的结合特异性，但它们在体内控制着不同的形态。这个悖论部分通过鉴定 Hox 低亲和力结合位点得到了解决。然而，前体 Hox 蛋白比后体 Hox 蛋白更加混杂，这就提出了一个问题，即前体 Hox 蛋白如何实现特异性。我们使用了 AP2x 增强子，它在头部的上颌段被 Hox 转录因子 Deformed（Dfd）激活。这个增强子缺乏典型的 Dfd-Exd 结合位点，但含有几个预测的低亲和力结合位点。出乎意料的是，这些结合位点被 Dfd-Exd 复合物强烈结合，而将它们转化为最优的 Dfd-Exd 结合位点只会导致结合强度略有增加。亲和力的这些微小变化改变了增强子对不同 Dfd 水平的敏感性，导致 AP-2 表达和上颌形态发生的紊乱。因此，Hox 调节的形态发生似乎是由于 Hox 结合亲和力和 Hox 剂量的共同进化，以实现对精确靶基因的调节。
