Functional partitioning of transcriptional regulators by patterned charge blocks

Components of transcriptional machinery are selectively partitioned into specific condensates, often mediated by protein disorder, yet we know little about how this specificity is achieved. Here, we show that condensates composed of the intrinsically disordered region (IDR) of MED1 selectively partition RNA polymerase II together with its positive allosteric regulators while excluding negative regulators. This selective compartmentalization is sufficient to activate transcription and is required for gene activation during a cell-state transition. The IDRs of partitioned proteins are necessary and sufficient for selective compartmentalization and require alternating blocks of charged amino acids. Disrupting this charge pattern prevents partitioning, whereas adding the pattern to proteins promotes partitioning with functional consequences for gene activation. IDRs with similar patterned charge blocks show similar partitioning and function. These findings demonstrate that disorder-mediated interactions can selectively compartmentalize specific functionally related proteins from a complex mixture of biomolecules, leading to regulation of a biochemical pathway. [Display omitted] •Disorder-mediated selective partitioning regulates gene activation•Disordered regions are necessary and sufficient for selective partitioning•Charge patterning in disordered regions is required for specificity of partitioning•Disordered regions with similar patterning have similar partitioning and function Charge patterning in disordered regions of transcriptional regulators mediates selective partitioning into MED1IDR condensates for gene activation.