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

• Published in: Nature cell biology Vol. 26; no. 8; pp. 1309 - 1321
• Main Authors: Naderi, Julian, Magalhaes, Alexandre P., Kibar, Gözde, 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
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.08.2024; Nature Publishing Group
• Subjects: 45; 45/15; 631/136; 631/208/200; Amino acids; Biomedical and Life Sciences; Cancer Research; Cell Biology; Cellular Reprogramming - genetics; Developmental Biology; DNA - genetics; DNA - metabolism; Gene Expression Regulation; Gene sequencing; HEK293 Cells; Humans; Intrinsically Disordered Proteins - chemistry; Intrinsically Disordered Proteins - genetics; Intrinsically Disordered Proteins - metabolism; Life Sciences; Liquid phases; Mutation; Nucleotide sequence; Phase separation; Protein Binding; Residues; Stem Cells; Tradeoffs; Transcription factors; Transcription Factors - genetics; Transcription Factors - metabolism; Transcription, Genetic
• ISSN: 1465-7392; 1476-4679; 1476-4679
• DOI: 10.1038/s41556-024-01411-0

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. Naderi et al. show that increasing the dispersion of aromatic residues in intrinsically disordered regions of human transcription factors enhances their activity but reduces their specificity.