Department of Biology, Center for Genomics and Systems Biology, New York University, New York, United States.
Memorial Sloan Kettering Cancer Center, New York, United States.
Elife. 2018 Apr 5;7:e32323. doi: 10.7554/eLife.32323.
We studied adaptive evolution of gene expression using long-term experimental evolution of in ammonium-limited chemostats. We found repeated selection for non-synonymous variation in the DNA binding domain of the transcriptional activator, GAT1, which functions with the repressor, DAL80 in an incoherent type-1 feedforward loop (I1-FFL) to control expression of the high affinity ammonium transporter gene, MEP2. Missense mutations in the DNA binding domain of GAT1 reduce its binding to the GATAA consensus sequence. However, we show experimentally, and using mathematical modeling, that decreases in GAT1 binding result in increased expression of MEP2 as a consequence of properties of I1-FFLs. Our results show that I1-FFLs, one of the most commonly occurring network motifs in transcriptional networks, can facilitate adaptive tuning of gene expression through modulation of transcription factor binding affinities. Our findings highlight the importance of gene regulatory architectures in the evolution of gene expression.
我们利用在铵限制的恒化器中进行的长期实验进化研究了基因表达的适应性进化。我们发现，在转录激活因子 GAT1 的 DNA 结合域中，非同义变异的选择是反复出现的，GAT1 与抑制剂 DAL80 一起在不连贯的 1 型前馈环 (I1-FFL) 中发挥作用，以控制高亲和力铵转运基因 MEP2 的表达。GAT1 的 DNA 结合域中的错义突变会降低其与 GATAA 共有序列的结合。然而，我们通过实验和数学建模表明，GAT1 结合的减少会导致 MEP2 的表达增加，这是 I1-FFL 的特性所致。我们的研究结果表明，I1-FFL 是转录网络中最常见的网络基序之一，它可以通过调节转录因子结合亲和力来促进基因表达的适应性调整。我们的研究结果强调了基因调控结构在基因表达进化中的重要性。
