Naderi, JulianMagalhaes, Alexandre P.Kibar, GözdeStik, GrégoireZhang, YaotianMackowiak, Sebastian D.Wieler, Hannah M.Rossi, FrancescaBuschow, ReneChristou-Kent, MarieAlcoverro-Bertran, MarcGraf, T. (Thomas)Vingron, MartinHnisz, Denes2024-09-232024-09-232024Naderi J, Magalhaes AP, Kibar G, Stik G, Zhang Y, Mackowiak SD, et al. An activity-specificity trade-off encoded in human transcription factors. Nat Cell Biol. 2024 Aug;26(8):1309-21. DOI: 10.1038/s41556-024-01411-01465-7392http://hdl.handle.net/10230/61198Transcription 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.application/pdfeng© The Author(s) 2024. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.info:eu-repo/semantics/articlehttp://dx.doi.org/10.1038/s41556-024-01411-0Developmental biologyGene regulationinfo:eu-repo/semantics/openAccess