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Heat shock induces premature transcript termination and reconfigures the human transcriptome.

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posted on 27.04.2022, 09:51 authored by Simona Cugusi, Richard Mitter, Gavin P Kelly, Jane Walker, Zhong Han, Paola Pisano, Michael Wierer, Aengus Stewart, Jesper Q Svejstrup
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.

Funding

Crick (Grant ID: 10002, Grant title: STP Bioinformatics & Biostatistics) Crick (Grant ID: 10166, Grant title: Svejstrup FC001166) European Research Council (Grant ID: 693327 - TRANSDAM, Grant title: ERC 693327 - TRANSDAM)

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