Rethinking transcription factor dynamics and transcription regulation in eukaryotes

Transcription factors (TFs) control gene expression by binding to specific DNA motifs in cis-regulatory elements. Cooperativity has been thought to ensure TF binding specificity. Recent research suggests that, at least in yeast, the role of cooperativity has probably been overemphasized. Consequently, synergy – the collective recruitment of the transcriptional machinery by TFs bound at multiple DNA sites – emerges as a more significant mechanism for achieving the specificity of the transcriptional response. Furthermore, I argue that the concentration of TFs within phase-separated nuclear condensates and their covalent modifications play an underappreciated but crucial role in sharpening transcriptional responses through complementary mechanisms. A model integrating cooperativity, synergy, post-translational modifications, and phase separation provides a comprehensive framework to explain dynamic, context-specific transcriptional responses in eukaryotes.