Zinc cluster transcription factors frequently activate target genes using a non-canonical half-site binding mode.
Zinc cluster transcription factors frequently activate target genes using a non-canonical half-site binding mode.
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DOI：
10.1093/nar/gkad320
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发表时间：
2023-06-09
影响因子：
14.9
通讯作者：
Mitra, Robi D.
中科院分区：
文献类型：
--
作者：
Recio, Pamela S.;Mitra, Nikhil J.;Shively, Christian A.;Song, David;Jaramillo, Grace;Lewis, Kristine Shady;Chen, Xuhua;Mitra, Robi D.
基因表达变化由转录因子（TF）协调，转录因子结合DNA以调节基因表达。它仍然令人惊讶地难以预测的转录过程的基本特征，包括在体内TF占用。现有的TF功能的热力学模型往往与实验测量不一致，这表明未发现的生物学。在这里，我们分析了一个最好的研究TF，酵母锌簇Gal 4，构建了一个Shea-Ackers热力学模型来描述其结合，并比较该模型的结果，实验测量的Gal 4p结合在体内。我们发现，在许多启动子，该模型预测没有Gal 4p结合，但观察到大量的结合。这些异常启动子缺乏典型的结合基序，随后的研究显示Gal 4p意外地结合到具有高密度的其半位点（CGG）的DNA序列。我们通过多种实验和计算范例证实了这种新的结合模式;我们还发现我们测试的大多数其他锌簇TF经常使用这种结合模式，平均占其靶点的27%。总之，这些结果证明了一种新的结合模式，其中锌簇，酵母中最大的一类TF，结合具有高密度半位点的DNA序列。芽殖酵母中一种新的非典型结合模式。
Gene expression changes are orchestrated by transcription factors (TFs), which bind to DNA to regulate gene expression. It remains surprisingly difficult to predict basic features of the transcriptional process, including in vivo TF occupancy. Existing thermodynamic models of TF function are often not concordant with experimental measurements, suggesting undiscovered biology. Here, we analyzed one of the most well-studied TFs, the yeast zinc cluster Gal4, constructed a Shea–Ackers thermodynamic model to describe its binding, and compared the results of this model to experimentally measured Gal4p binding in vivo. We found that at many promoters, the model predicted no Gal4p binding, yet substantial binding was observed. These outlier promoters lacked canonical binding motifs, and subsequent investigation revealed Gal4p binds unexpectedly to DNA sequences with high densities of its half site (CGG). We confirmed this novel mode of binding through multiple experimental and computational paradigms; we also found most other zinc cluster TFs we tested frequently utilize this binding mode, at 27% of their targets on average. Together, these results demonstrate a novel mode of binding where zinc clusters, the largest class of TFs in yeast, bind DNA sequences with high densities of half sites. A novel mode of non-canonical binding in budding yeast.
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