Integrator is a genome-wide attenuator of non-productive transcription

Termination of RNA polymerase II (RNAPII) transcription in metazoans relies largely on the Cleavage and Polyadenylation (CPA) and Integrator (INT) complexes originally found to act at the ends of protein-coding and snRNA genes, respectively. Here we monitor CPA- and INT-dependent termination activities genome-wide, including at thousands of previously unannotated transcription units (TUs), producing unstable RNA. We verify the global activity of CPA, occurring at pA sites indiscriminately of their positioning relative to the TU promoter. We also identify a global activity of INT, which is, however, largely sequence-independent and restricted to a ~3 kb promoter-proximal region. Our analyses suggest two functions of genome-wide INT activity; it dampens transcriptional output from weak promoters and it provides quality-control of RNAPII complexes that are unfavorably configured for transcriptional elongation. We suggest that the function of INT in stable snRNA production is an exception from its general cellular role, the attenuation of non-productive transcription. Cleavage and polyadenylation complex subunit CPFS3, Integrator complex subunit IntS11, Exosome complex subunit EXOSC3 were knocked down in HeLa cells using siRNA. The corresponding controls were the non-tageting EGFP or Luc siRNA knockdown. Two biological replicates were generated for TT-seq and RNA-seq. Three biological replicates were generated for 3'-seq.