The super elongation complex (SEC) mediates phase transition of SPT5 during transcriptional pause release

Release of promoter‐proximally paused RNA Pol II into elongation is a tightly regulated and rate‐limiting step in metazoan gene transcription. However, the biophysical mechanism underlying pause release remains unclear. Here, we demonstrate that the pausing and elongation regulator SPT5 undergoes phase transition during transcriptional pause release. SPT5 per se is prone to form clusters. The disordered domain in SPT5 is required for pause release and gene activation. During early elongation, the super elongation complex (SEC) induces SPT5 transition into elongation droplets. Depletion of SEC increases SPT5 pausing clusters. Furthermore, disease‐associated SEC mutations impair phase properties of elongation droplets and transcription. Our study suggests that SEC‐mediated SPT5 phase transition might be essential for pause release and early elongation and that aberrant phase properties could contribute to transcription abnormality in diseases. Synopsis The super elongation complex (SEC) induces phase transition of SPT5 from pausing clusters into elongation droplets. Disease‐associated SEC mutations impair phase properties of the elongation droplets and transcription. SPT5 has an intrinsic property to form clusters, and its disordered domain is required for pause release and gene activation. SEC promotes SPT5 relocation from pausing clusters into elongation droplets. Diseases‐associated SEC mutations alter the phase properties of the elongation droplets Graphical Abstract The super elongation complex (SEC) induces phase transition of SPT5 from pausing clusters into elongation droplets. Disease‐associated SEC mutations impair phase properties of the elongation droplets and transcription.