DNA-binding specificity changes in the evolution of forkhead transcription factors
DNA-binding specificity changes in the evolution of forkhead transcription factors
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DOI：
10.1073/pnas.1310430110
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发表时间：
2013-07-23
影响因子：
11.1
通讯作者：
Bulyk, Martha L.
中科院分区：
文献类型：
--
作者：
Nakagawa, So;Gisselbrecht, Stephen S.;Bulyk, Martha L.
转录调控网络的进化需要转录因子（TF）家族的扩展和多样化。由高度保守的翼螺旋DNA结合结构域（DBD）定义的TF的叉头家族在动物、真菌和相关原生生物中已经分化成数十个亚家族。我们已经使用了最大似然系统发育推断和独立的，全面的DNA结合能力的功能测定相结合，探讨叉头家族内的DNA结合特异性的演变。我们提出了趋同的证据表明，类似的替代序列偏好已经出现反复和独立的过程中的叉头进化。我们观察到的绝大多数DNA结合特异性变化不能用已知的赋予典型叉头结合位点特异性的DNA接触氨基酸残基的改变来解释。有趣的是，我们发现叉头DBD保留了非常特异性地结合两个完全不同的DNA序列基序的能力。我们提出了一种替代的特异性决定机制，即DBD的构象重排拓宽了TF可以识别的序列基序的谱。DNA结合的双特异性表明一个以前未描述的来源的模块性和灵活性的基因调控，并可能在转录调控网络的演变中发挥重要作用。
The evolution of transcriptional regulatory networks entails the expansion and diversification of transcription factor (TF) families. The forkhead family of TFs, defined by a highly conserved winged helix DNA-binding domain (DBD), has diverged into dozens of subfamilies in animals, fungi, and related protists. We have used a combination of maximum-likelihood phylogenetic inference and independent, comprehensive functional assays of DNA-binding capacity to explore the evolution of DNA-binding specificity within the forkhead family. We present converging evidence that similar alternative sequence preferences have arisen repeatedly and independently in the course of forkhead evolution. The vast majority of DNA-binding specificity changes we observed are not explained by alterations in the known DNA-contacting amino acid residues conferring specificity for canonical forkhead binding sites. Intriguingly, we have found forkhead DBDs that retain the ability to bind very specifically to two completely distinct DNA sequence motifs. We propose an alternate specificity-determining mechanism whereby conformational rearrangements of the DBD broaden the spectrum of sequence motifs that a TF can recognize. DNA-binding bispecificity suggests a previously undescribed source of modularity and flexibility in gene regulation and may play an important role in the evolution of transcriptional regulatory networks.