荷兰伊拉斯谟大学Joris Pothof研究小组发现，在衰老过程中，全基因组RNA聚合酶的停滞改变转录组。2023年1月19日，《自然—遗传学》杂志在线发表了这项成果。

研究人员将新生RNA测序和RNA聚合酶II染色质免疫沉淀结合起来，然后进行测序，以阐明触发野生型衰老小鼠基因表达变化的潜在机制。研究人员发现，在2岁的肝脏中，40%的延长RNA聚合酶处于停滞状态，降低了生产转录，并以基因长度依赖的方式扭曲了转录输出。研究人员人员证明，这种转录应激是由内源性DNA损伤引导的，并解释了大多数主要有丝分裂后器官中衰老过程中的大多数基因表达变化，特别是影响衰老标志通路，如营养感应、自噬、蛋白质稳态、能量代谢、免疫功能和细胞应激恢复能力。从线虫到人类，与年龄相关的转录应激是演化保守的。因此，衰老过程中随机内基因DNA损伤的积累会恶化基础转录，这建立了与年龄相关的转录组和关键衰老标志通路的功能障碍，并揭示了DNA损伤如何在功能上构成正常衰老的主要方面。

据了解，基因表达谱已经确定了许多在衰老过程中发生变化的过程，但这些变化是如何发生的在很大程度上是未知的。

附：英文原文

Title: Genome-wide RNA polymerase stalling shapes the transcriptome during aging

Author: Gyenis, Akos, Chang, Jiang, Demmers, Joris J. P. G., Bruens, Serena T., Barnhoorn, Sander, Brandt, Renata M. C., Baar, Marjolein P., Raseta, Marko, Derks, Kasper W. J., Hoeijmakers, Jan H. J., Pothof, Joris

Issue&Volume: 2023-01-19

Abstract: Gene expression profiling has identified numerous processes altered in aging, but how these changes arise is largely unknown. Here we combined nascent RNA sequencing and RNA polymerase II chromatin immunoprecipitation followed by sequencing to elucidate the underlying mechanisms triggering gene expression changes in wild-type aged mice. We found that in 2-year-old liver, 40% of elongating RNA polymerases are stalled, lowering productive transcription and skewing transcriptional output in a gene-length-dependent fashion. We demonstrate that this transcriptional stress is caused by endogenous DNA damage and explains the majority of gene expression changes in aging in most mainly postmitotic organs, specifically affecting aging hallmark pathways such as nutrient sensing, autophagy, proteostasis, energy metabolism, immune function and cellular stress resilience. Age-related transcriptional stress is evolutionary conserved from nematodes to humans. Thus, accumulation of stochastic endogenous DNA damage during aging deteriorates basal transcription, which establishes the age-related transcriptome and causes dysfunction of key aging hallmark pathways, disclosing how DNA damage functionally underlies major aspects of normal aging.

DOI: 10.1038/s41588-022-01279-6

Source: https://www.nature.com/articles/s41588-022-01279-6