Stress-induced transcriptional memory accelerates promoter-proximal pause release and decelerates termination over mitotic divisions

• Published in: Molecular cell 2021-04, Vol.81 (8), p.1715-1731.e6
• Main Authors: Vihervaara, Anniina, Mahat, Dig Bijay, Himanen, Samu V., Blom, Malin A.H., Lis, John T., Sistonen, Lea
• Format: Article
• Language: English
• Subjects: acquired stress resistance; Cell Line, Tumor; Chromatin - genetics; chromatin accessibility; enhancer transcription; Fibroblasts - physiology; Gene Expression Regulation - genetics; gene-enhancer networks; Genome - genetics; Heat-Shock Response - genetics; Humans; K562 Cells; Mitosis - genetics; nascent transcription program; Pol II pausing; progression of Pol II; Promoter Regions, Genetic - genetics; recycling of Pol II; RNA Polymerase II - genetics; RNA, Messenger - genetics; Stress, Physiological - genetics; transcription termination; Transcription, Genetic - genetics
• ISSN: 1097-2765; 1097-4164; 1097-4164
• DOI: 10.1016/j.molcel.2021.03.007

Heat shock instantly reprograms transcription. Whether gene and enhancer transcription fully recover from stress and whether stress establishes a memory by provoking transcription regulation that persists through mitosis remained unknown. Here, we measured nascent transcription and chromatin accessibility in unconditioned cells and in the daughters of stress-exposed cells. Tracking transcription genome-wide at nucleotide-resolution revealed that cells precisely restored RNA polymerase II (Pol II) distribution at gene bodies and enhancers upon recovery from stress. However, a single heat exposure in embryonic fibroblasts primed a faster gene induction in their daughter cells by increasing promoter-proximal Pol II pausing and by accelerating the pause release. In K562 erythroleukemia cells, repeated stress refined basal and heat-induced transcription over mitotic division and decelerated termination-coupled pre-mRNA processing. The slower termination retained transcripts on the chromatin and reduced recycling of Pol II. These results demonstrate that heat-induced transcriptional memory acts through promoter-proximal pause release and pre-mRNA processing at transcription termination. [Display omitted] •Cell-type-specific transcription precisely recovers after heat shock•Daughters of stressed cells accelerate heat induction of quality control genes•Daughters of repeatedly stressed cells refine basal and inducible transcription•Transcriptional memory acts at Pol II pause release and transcription termination Heat shock reprograms transcription at genes and enhancers. Vihervaara et al. reveal that cells precisely restore transcription program after heat exposure and that cells establish a transcriptional memory of stress. In the daughters of stressed cells, increased Pol II pause release accelerates gene activation and reduced transcription termination decelerates mRNA processing.