Gene expression profiling of replicative and induced senescence

Cellular senescence is a cell cycle arrest accompanied by high expression of cyclin dependent kinase inhibitors which counteract overactive growth signals, which serves as a tumor suppressive mechanism. Senescence can be a result of telomere shortening (natural or replicative senescence) or DNA damage resulting from exogenous stressors (induced senescence). Here, we performed gene expression profiling through RNA-seq of replicative senescence, adriamycin-induced senescence, H₂O₂-induced senescence, and 5-aza-2-deoxycytidine-induced senescence in order to profile the pathways controlling various types of senescence. Overall, the pathways common to all 4 types of senescence were related to inflammation and the innate immune system. It was also evident that 5-aza-induced senescence mirrors natural replicative senescence due to telomere shortening. We also examined the prevalence of senescence-associated secretory phenotype (SASP) factors in the RNA-seq data, showing that it is a common characteristic of all 4 types of senescence. In addition, we could discriminate changes in gene expression due to quiescence during cellular senescence from those that were specific to senescence.

细胞衰老（cellular senescence）是一类伴随细胞周期蛋白依赖性激酶抑制剂（cyclin dependent kinase inhibitors）高表达的细胞周期阻滞现象，可抵消过度激活的生长信号，属于一种肿瘤抑制机制。衰老的诱因可分为两类：一是端粒缩短（telomere shortening）引发的自然衰老或复制性衰老；二是外源性应激源（exogenous stressors）导致DNA损伤所引发的诱导性衰老。本研究通过RNA测序（RNA-seq）对复制性衰老、阿霉素（adriamycin）诱导衰老、过氧化氢（H₂O₂）诱导衰老以及5-氮杂-2'-脱氧胞苷（5-aza-2-deoxycytidine）诱导衰老开展基因表达谱分析，以系统解析调控不同类型衰老的信号通路。整体而言，四种衰老类型共有的信号通路均与炎症及先天免疫系统密切相关。研究同时发现，5-氮杂诱导的衰老可模拟因端粒缩短导致的自然复制性衰老。此外，本研究还对衰老相关分泌表型（SASP）因子在RNA-seq数据中的分布丰度进行了分析，证实该表型是四种衰老类型的共同特征。进一步地，本研究能够区分细胞衰老过程中由静息状态（quiescence）介导的基因表达变化，与衰老特异性的基因表达变化。