Stress-Induced Transcriptional Memory Accelerates Promoter-Proximal Pause-Release and Decelerates Termination over Mitotic Divisions

Anniina Vihervaara; Dig Bijay Mahat; Samu V. Himanen; Malin A.H. Blom; John T. Lis; Lea Sistonen

Here, we measured transcriptional response to acute heat stress in unconditioned cells and in 22! daughters of cells that had been exposed to a single or multiple heat shocks. Tracking RNA 23! Polymerase II (Pol II) genome-wide at nucleotide-resolution revealed that cells precisely 24! remember their transcriptional identity throughout stress, restoring Pol II distribution at gene 25! bodies and enhancers upon recovery. However, single heat shock primed faster gene-induction in 26! the daughter cells by increasing promoter-proximal Pol II pausing, and accelerating the pause-27! release. In repeatedly stressed cells, both basal and inducible transcription was refined, and pre-28! mRNA processing decelerated, which retained transcripts on chromatin and reduced recycling of Heat shock is one of the most potent triggers of transcription reprogramming, provoking an 47! instant and genome-wide change in RNA synthesis from genes and enhancers (reviewed in 48! Vihervaara et al., 2018) . Upon heat shock, hundreds of genes are rapidly induced by potent trans-49! activators, such as Heat Shock Factor 1 (HSF1). When activated, HSF1 binds to Heat Shock 50! Elements (HSEs) at architecturally primed promoters and enhancers (Rougvie and Lis, 1988; 51! Rasmussen and Lis, 1993; Guertin and Lis, 2010; Ray et al., 52! 2019) , and it can trigger the release of promoter-proximally paused Pol II into productive 53! elongation Mahat et al., 2016) . Concomitantly with the heat-induced escape 54! of Pol II from the promoters of activated genes, thousands of genes are repressed via inhibition of 55! the pause-release. This repression leads to the accumulation Pol II at promoter-proximal regions 56! and clears transcription complexes from gene bodies Vihervaara et al., 57! 2017) . As a consequence of the genome-wide re-coordination of Pol II pause-release, heat-58! stressed cells promptly switch their transcription program to produce chaperones and protect 59! cellular integrity. 60!