德国马克斯·普朗克分子遗传学研究所Denes Hnisz和Martin Vingron团队提出了人类转录因子编码的活性-特异性平衡。这一研究成果发表在2024年7月5日出版的国际学术期刊《自然—细胞生物学》上。

据了解，转录因子(Transcription factors, TFs)控制着基因转录的特异性和活性，但这两者之间是否存在关系尚不清楚。

研究组表明在人类转录因子中，活性和特异性之间存在进化上的平衡，这表现为它们在其本征无序蛋白区域中芳香族残基的亚最大分散。课题组研究人员鉴定了大约500个人类转录因子，在其本征无序区域中编码了短周期的芳香族残基块，类似于不完全的朊病毒样序列。

周期性芳香残基的突变降低了转录活性，而增加多种人转录因子的芳香分散则提高了转录活性和重编程效率，促进了体外液-液相分离和细胞内更多的混杂DNA结合。结合最近对增强子元件的研究，这些结果表明，次优特征在转录控制中具有重要的进化作用。课题组人员提出，改变相分离的氨基酸特征的合理工程，可能是优化转录因子依赖过程的一种策略，包括细胞重编程。

附：英文原文

Title: An activity-specificity trade-off encoded in human transcription factors

Author: Naderi, Julian, Magalhaes, Alexandre P., Kibar, Gzde, Stik, Gregoire, Zhang, Yaotian, Mackowiak, Sebastian D., Wieler, Hannah M., Rossi, Francesca, Buschow, Rene, Christou-Kent, Marie, Alcoverro-Bertran, Marc, Graf, Thomas, Vingron, Martin, Hnisz, Denes

Issue&Volume: 2024-07-05

Abstract: 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.

DOI: 10.1038/s41556-024-01411-0

Source: https://www.nature.com/articles/s41556-024-01411-0