Transcription factors (TFs) control specificity and activity of gene transcription, but whether a relationship between these two features exists is unclear. Here we provide evidence for an evolutionary trade-off between the activity and specificity in human TFs encoded as submaximal dispersion of aromatic residues in their intrinsically disordered protein regions. We identified approximately 500 human TFs that encode short periodic blocks of aromatic residues in their intrinsically disordered regions, resembling imperfect prion-like sequences. Mutation of periodic aromatic residues reduced transcriptional activity, whereas increasing the aromatic dispersion of multiple human TFs enhanced transcriptional activity and reprogramming efficiency, promoted liquid–liquid phase separation in vitro and more promiscuous DNA binding in cells. Together with recent work on enhancer elements, these results suggest an important evolutionary role of suboptimal features in transcriptional control. We propose that rational engineering of amino acid features that alter phase separation may be a strategy to optimize TF-dependent processes, including cellular reprogramming.

转录因子（TF）控制基因转录的特异性和活性，但这两个特征之间是否存在关系尚不清楚。在这里，我们为人类转录因子的活性和特异性之间的进化权衡提供了证据，编码为芳香族残基在其本质上无序的蛋白质区域中的次最大分散。我们鉴定了大约 500 个人类转录因子，它们在其本质上无序的区域中编码芳香族残基的短周期块，类似于不完美的朊病毒样序列。周期性芳香残基的突变降低了转录活性，而增加多个人类转录因子的芳香分散性则增强了转录活性和重编程效率，促进了体外液-液相分离以及细胞中更混杂的DNA结合。结合最近关于增强子元件的研究，这些结果表明次优特征在转录控制中的重要进化作用。我们提出，改变相分离的氨基酸特征的合理工程可能是优化 TF 依赖性过程（包括细胞重编程）的策略。