Integrator regulates transcriptional initiation and pause release following activation

In unicellular organisms, initiation is the rate-limiting step in transcription; in metazoan organisms, the transition from initiation to productive elongation is also important. Here, we show that the RNA polymerase II (RNAPII)-associated multiprotein complex, Integrator, plays a critical role in both initiation and the release of paused RNAPII at immediate early genes (IEGs) following transcriptional activation by epidermal growth factor (EGF) in human cells. Integrator is recruited to the IEGs in a signal-dependent manner and is required to engage and recruit the super elongation complex (SEC) to EGF-responsive genes to allow release of paused RNAPII and productive transcription elongation. •Integrator is recruited to protein-coding genes•Loss of Integrator abrogates immediate early gene responsiveness to EGF•Integrator plays a role in transcription initiation and pause release•Integrator physically associates with the SEC complex. Gardini etal. show that Integrator recruits the SEC complex to protein-coding genes, facilitating stimulus-dependent transcription activation and release of paused RNA polymerase for productive transcription elongation.