Stress-Induced Transcriptional Memory Accelerates Promoter-Proximal Pause-Release and Decelerates Termination over Mitotic Divisions
Stress-Induced Transcriptional Memory Accelerates Promoter-Proximal Pause-Release and Decelerates Termination over Mitotic Divisions
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DOI：
10.1101/576959
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发表时间：
2019-03
期刊：
影响因子：
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通讯作者：
Anniina Vihervaara;Dig B. Mahat;Samu V. Himanen;Malin A H Blom;J. Lis;L. Sistonen
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文献类型：
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作者：
Anniina Vihervaara;Dig B. Mahat;Samu V. Himanen;Malin A H Blom;J. Lis;L. Sistonen
热休克会触发基因和增强子转录的即时重编程，但细胞是否在新生转录水平上编码应激记忆仍然未知。在这里，我们测量了未条件化细胞和暴露于单次或多次热休克的细胞子代中对急性热应激的转录反应。以核苷酸分辨率在全基因组范围内追踪 RNA 聚合酶 II (Pol II) 表明，细胞在整个应激过程中精确地记住了它们的转录身份，在恢复后恢复了基因体和增强子上的 Pol II 分布。然而，单次热激通过增加启动子近端 Pol II 暂停并加速暂停释放，在子细胞中引发更快的基因诱导。在反复应激的细胞中，基础转录和诱导转录均得到改善，前体 mRNA 加工速度减慢，从而保留了染色质上的转录本并减少了转录机制的循环利用。这些结果从机制上揭示了暂停-释放和终止步骤如何在有丝分裂过程中维持转录记忆。亮点 -细胞类型特异性转录在热诱导重编程后精确恢复 -单次热激启动基因，通过增加启动子近端 Pol II 暂停和更快的暂停释放来加速诱导有丝分裂分裂 -多次热激细化有丝分裂分裂的基础转录和诱导转录，以支持子细胞的存活 -活性基因的减速终止减少了 Pol II 向热激活启动子和增强子的再循环 -HSF1 增加了有丝分裂分裂的速率通过远端和近端调节元件启动子-近端暂停-释放
Heat shock triggers an instant reprogramming of gene and enhancer transcription, but whether cells encode a memory to stress, at the level of nascent transcription, has remained unknown. Here, we measured transcriptional response to acute heat stress in unconditioned cells and in daughters of cells that had been exposed to a single or multiple heat shocks. Tracking RNA Polymerase II (Pol II) genome-wide at nucleotide-resolution revealed that cells precisely remember their transcriptional identity throughout stress, restoring Pol II distribution at gene bodies and enhancers upon recovery. However, single heat shock primed faster gene-induction in the daughter cells by increasing promoter-proximal Pol II pausing, and accelerating the pause-release. In repeatedly stressed cells, both basal and inducible transcription was refined, and pre-mRNA processing decelerated, which retained transcripts on chromatin and reduced recycling of the transcription machinery. These results mechanistically uncovered how the steps of pause-release and termination maintain transcriptional memory over mitosis. Highlights -Cell type-specific transcription precisely recovers after heat-induced reprogramming -Single heat shock primes genes for accelerated induction over mitotic divisions via increased promoter-proximal Pol II pausing and faster pause-release -Multiple heat shocks refine basal and inducible transcription over mitotic divisions to support survival of the daughter cells -Decelerated termination at active genes reduces recycling of Pol II to heat-activated promoters and enhancers -HSF1 increases the rate of promoter-proximal pause-release via distal and proximal regulatory elements