Pan-senescence transcriptome analysis identified RRAD as a marker and negative regulator of cellular senescence
Pan-senescence transcriptome analysis identified RRAD as a marker and negative regulator of cellular senescence
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泛衰老转录组分析确定 RRAD 是细胞衰老的标记物和负调节因子
DOI：
10.1016/j.freeradbiomed.2018.10.457
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发表时间：
2019
影响因子：
7.4
通讯作者：
Shao Changshun
中科院分区：
文献类型：
--
作者：
Wei Zhao;Guo Haiyang;Qin Junchao;Lu Shihua;Liu Qiao;Zhang Xiyu;Zou Yongxin;Gong Yaoqin;Shao Changshun
细胞衰老是一种不可逆转的增殖停滞，在发育过程中参与组织重塑，并与多种衰老相关疾病有关。虽然衰老细胞通常表现出一系列与衰老相关的表型，如细胞周期停滞、异染色质结构改变、重新编程的代谢和衰老相关的分泌表型(SASP)，但由于缺乏特异和通用的生物标志物，衰老细胞的鉴定一直受到阻碍。为了系统地识别细胞衰老的通用生物标志物，我们整合了通过不同体外操作模式获得的衰老细胞的多个转录组数据集以及人体组织与年龄相关的基因表达数据。我们的分析表明，RRAD(与糖尿病相关的RAS)在所有的操作模式中都表达上调，并且在人类皮肤和脂肪组织中随着年龄的增长而增加。Ras、H_2O_2、电离辐射、羟基脲、依托泊苷和复制传代分别诱导衰老的人成纤维细胞RRAD表达增强。进一步的功能研究表明，RRAD上调作为一种负反馈机制，通过降低活性氧水平来对抗细胞衰老。最后，我们发现P53和NF-κB都与RRAD基因组区域结合并调控RRAD的转录。本研究确定RRAD是一种生物标志物，也是一种新的细胞衰老负调控因子。
Cellular senescence, an irreversible proliferative arrest, functions in tissue remodeling during development and is implicated in multiple aging-associated diseases. While senescent cells often manifest an array of senescence-associated phenotypes, such as cell cycle arrest, altered heterochromatin architecture, reprogrammed metabolism and senescence-associated secretory phenotype (SASP), the identification of senescence cells has been hindered by lack of specific and universal biomarkers. To systematically identify universal biomarkers of cellular senescence, we integrated multiple transcriptome data sets of senescent cells obtained through different in vitro manipulation modes as well as age-related gene expression data of human tissues. Our analysis showed thatRRAD(Ras-related associated with diabetes) expression is up-regulated in all the manipulation modes and increases with age in human skin and adipose tissues. The elevated RRAD expression was then confirmed in senescent human fibroblasts that were induced by Ras, H2O2, ionizing radiation, hydroxyurea, etoposide and replicative passage, respectively. Further functional study suggests that RRAD up-regulation acts as a negative feedback mechanism to counter cellular senescence by reducing the level of reactive oxygen species. Finally, we found both p53 and NF-κB bind toRRADgenomic regions and modulateRRADtranscription. This study established RRAD to be a biomarker as well as a novel negative regulator of cellular senescence.