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

Affiliations
  • 1Department of Genome Regulation, Max Planck Institute for Molecular Genetics, Berlin, Germany.
  • 2Institute of Chemistry and Biochemistry, Department of Biology, Chemistry and Pharmacy, Freie Universität Berlin, Berlin, Germany.
  • 3Department of Computational Molecular Biology, Max Planck Institute for Molecular Genetics, Berlin, Germany.
  • 4Centre for Genomic Regulation, The Barcelona Institute of Science and Technology, Barcelona, Spain.
  • 5Josep Carreras Leukaemia Research Institute, Badalona, Spain.
  • 6Microscopy Core Facility, Max Planck Institute for Molecular Genetics, Berlin, Germany.
  • 7Universitat Pompeu Fabra, Barcelona, Spain.
  • 8Department of Genome Regulation, Max Planck Institute for Molecular Genetics, Berlin, Germany. hnisz@molgen.mpg.de.

Published on:

July 5, 2024

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.

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