Heat shock induces premature transcript termination and reconfigures the human transcriptome

The heat shock (HS) response involves rapid induction of HS genes, whereas transcriptional repression is established more slowly at most other genes. Previous data suggested that such repression results from inhibition of RNA polymerase II (RNAPII) pause release, but here, we show that HS strongly affects other phases of the transcription cycle. Intriguingly, while elongation rates increase upon HS, processivity markedly decreases, so that RNAPII frequently fails to reach the end of genes. Indeed, HS results in widespread premature transcript termination at cryptic, intronic polyadenylation (IPA) sites near gene 5′-ends, likely via inhibition of U1 telescripting. This results in dramatic reconfiguration of the human transcriptome with production of new, previously unannotated, short mRNAs that accumulate in the nucleus. Together, these results shed new light on the basic transcription mechanisms induced by growth at elevated temperature and show that a genome-wide shift toward usage of IPA sites can occur under physiological conditions. [Display omitted] •Transcription downregulation during HS is caused by premature termination•Transcription elongation rate increases markedly during HS•HS disrupts telescripting and activates cryptic poly(A) sites in introns•HS results in widespread synthesis of new, short mRNAs species Cugusi et al. show that the elongation rate is dramatically increased during heat shock, while the global downregulation of transcription observed under these conditions is caused by premature termination at cryptic PAS in introns, which results in the synthesis of a large number of new, short mRNA species.