Selective phase separation of transcription factors is driven by orthogonal molecular grammar

Protein production is critically dependent on gene transcription rates, which are regulated by RNA polymerase and a large collection of different transcription factors (TFs). How these transcription factors selectively address different genes is only partially known. Recent discoveries show that the differential condensation of separate TF families through phase separation may contribute to selectivity. Here we address this by conducting phase separation studies on six TFs from three different TF families with residue-scale coarse-grained molecular dynamics simulations. Our exploration of ternary TF phase diagrams reveals four dominant sticker motifs and two orthogonal driving forces that dictate the resultant condensate morphology, pointing to sequence-dependent orthogonal molecular grammar as a generic molecular mechanism that drives selective transcriptional condensation in gene expression.