Aging is associated with increased chromatin accessibility and reduced polymerase pausing in liver [RNA-seq]

Regulation of gene expression is linked to the organization of the genome. With age, chromatin alterations occur on all levels of genome organization, accompanied by changes in the gene expression profile. However, little is known about the changes on the level of transcriptional regulation. Here, we used a multi-omics approach and integrated ATAC-, RNA- and NET-seq to identify age-related changes in the chromatin landscape of murine liver and to investigate how these are linked to transcriptional regulation. We provide the first systematic inventory of the connection between aging, chromatin accessibility and transcriptional regulation in a whole tissue. Aging in murine liver is characterized by an increase in chromatin accessibility at promoter regions, but not in an increase of transcriptional output. Instead, aging is accompanied by a decrease of promoter-proximal pausing of RNA polymerase II (Pol II), while initiation of transcription is not decreased as assessed by RNA polymerase mapping using CUT&RUN. Based on the data reported we propose that these age-related changes in transcriptional regulation are due to a reduced stability of the pausing complex. RNA-seq of murine liver tissue using 3 biological replicates per age group and 3 age groups (3,12 and 18 months)基因表达调控与基因组的组织架构紧密关联。随着衰老进程推进，染色质在基因组组织的所有层级均会发生改变，并伴随基因表达谱的变化。然而，当前学界对转录调控层面的年龄相关改变仍缺乏深入认知。本研究采用多组学研究策略，整合ATAC-seq、RNA-seq及NET-seq技术，以小鼠肝脏为研究模型，鉴定衰老相关的染色质景观变化，并探究这些变化与转录调控的关联机制。我们首次完成了完整组织中衰老、染色质可及性与转录调控三者间关联的系统性梳理。小鼠肝脏的衰老特征表现为启动子区域的染色质开放度升高，但转录输出量并未同步增加。与之相反，衰老伴随RNA聚合酶II（Pol II）的启动子近端暂停现象减弱，而通过CUT&RUN技术开展RNA聚合酶定位分析可知，转录起始过程并未出现降低。基于本研究产生的数据，我们提出：上述转录调控的年龄相关改变，源于暂停复合物稳定性的降低。本研究针对3个年龄组（3月龄、12月龄与18月龄）的小鼠肝脏组织进行RNA测序，每组设置3个生物学重复。