Transcription machinery clustering by Integrator synchronizes histone gene expression

Whether these clusters assemble on demand during transcription or constitute regulatory units remains unclear. Examining the Drosophila histone locus—where histone genes normally transcribe exclusively during S phase—we unexpectedly found large clusters containing non-chromatin-bound Pol II and elongation factors outside of S phase.

When transcription activates during S phase, P-TEFb drives an accelerated turnover of the cluster components. Dispersion of clusters through depletion of the Integrator complex endonuclease module causes histone transcription to have a diminished S-phase peak and instead occur ectopically throughout the cell cycle. We propose that clusters constitute gate-keeping hubs that maintain a poised machinery pool, restricting gene activation to defined temporal windows.