McKeown Alesia N, Bridgham Jamie T, Anderson Dave W, Murphy Michael N, Ortlund Eric A, Thornton Joseph W
Institute of Ecology and Evolution, University of Oregon, Eugene, OR 97403, USA.
Department of Biochemistry, Emory University, Atlanta, GA 30322, USA.
Cell. 2014 Sep 25;159(1):58-68. doi: 10.1016/j.cell.2014.09.003.
Complex gene regulatory networks require transcription factors (TFs) to bind distinct DNA sequences. To understand how novel TF specificity evolves, we combined phylogenetic, biochemical, and biophysical approaches to interrogate how DNA recognition diversified in the steroid hormone receptor (SR) family. After duplication of the ancestral SR, three mutations in one copy radically weakened binding to the ancestral estrogen response element (ERE) and improved binding to a new set of DNA sequences (steroid response elements, SREs). They did so by establishing unfavorable interactions with ERE and abolishing unfavorable interactions with SRE; also required were numerous permissive substitutions, which nonspecifically improved cooperativity and affinity of DNA binding. Our findings indicate that negative determinants of binding play key roles in TFs' DNA selectivity and-with our prior work on the evolution of SR ligand specificity during the same interval-show how a specific new gene regulatory module evolved without interfering with the integrity of the ancestral module.
复杂的基因调控网络需要转录因子（TFs）结合不同的DNA序列。为了理解新的TF特异性是如何进化的，我们结合了系统发育、生化和生物物理方法，来探究类固醇激素受体（SR）家族中DNA识别是如何多样化的。在祖先SR基因复制后，其中一个拷贝中的三个突变极大地削弱了与祖先雌激素反应元件（ERE）的结合，并增强了与一组新的DNA序列（类固醇反应元件，SREs）的结合。这些突变通过与ERE建立不利的相互作用，并消除与SRE的不利相互作用来实现这一点；还需要大量的允许性取代，这些取代非特异性地提高了DNA结合的协同性和亲和力。我们的研究结果表明，结合的负向决定因素在TFs的DNA选择性中起关键作用，并且——与我们之前关于同一时期SR配体特异性进化的研究一起——展示了一个特定的新基因调控模块是如何在不干扰祖先模块完整性的情况下进化的。
