Transcriptome Signature of Cellular Senescence

Abstract: Cellular senescence, an integral component of aging and cancer, arises in response to diverse triggers, including telomere attrition, macromolecular damage, and signaling from activated oncogenes. At present, senescent cells are identified by the combined presence of multiple traits, such as senescence-associated protein expression and secretion, DNA damage, and β-galactosidase activity; unfortunately, these traits are neither exclusively nor universally present in senescent cells. To identify robust shared markers of senescence, we have performed RNA-sequencing analysis across 8 diverse models of senescence triggered in human diploid fibroblasts (WI-38, IMR-90) and endothelial cells (HUVEC, HAEC) by replicative exhaustion, exposure to ionizing radiation or doxorubicin, and expression of the oncogene HRASG12V. The intersection of the altered transcriptomes revealed 47 RNAs consistently elevated and 26 RNAs consistently reduced across all senescence models, including many protein-coding mRNAs and some long noncoding RNAs. We propose that these shared transcriptome profiles will enable the identification of senescent cells in vivo, the investigation of their roles in aging and malignancy, and the development of strategies to target senescent cells therapeutically.

摘要：细胞衰老（cellular senescence）是衰老进程与癌症发生发展中不可或缺的组成部分，其产生源于端粒磨损、大分子损伤、激活癌基因信号传导等多种触发因素。目前，衰老细胞的鉴定需结合多项特征，例如衰老相关蛋白的表达与分泌、DNA损伤以及β-半乳糖苷酶活性；但遗憾的是，这些特征既非衰老细胞所特有，也并非在所有衰老细胞中均存在。为鉴定衰老细胞的稳健共享标志物，我们针对人类二倍体成纤维细胞（WI-38、IMR-90）与内皮细胞（HUVEC、HAEC）中由复制耗竭、电离辐射处理、阿霉素处理以及癌基因HRASG12V表达所诱导的8种不同衰老模型，开展了RNA测序（RNA-sequencing）分析。对各模型的差异转录组进行交集分析后发现，在所有衰老模型中，共有47种RNA持续上调，26种RNA持续下调，其中包含大量编码蛋白的mRNA以及部分长链非编码RNA（long noncoding RNAs）。我们认为，这些共享的转录组特征将可用于实现体内衰老细胞的鉴定、研究其在衰老与恶性肿瘤中的作用，并开发靶向衰老细胞的治疗策略。

搜集汇总

背景与挑战

背景概述

该数据集通过RNA测序分析，在人类二倍体成纤维细胞和内皮细胞的8种不同衰老模型中，识别了细胞衰老的共享转录组特征，包括47个一致上调RNA和26个一致下调RNA。这些发现为在体内识别衰老细胞、研究其在衰老和癌症中的角色以及开发靶向治疗策略提供了基础。