Human senescence PRO-cap

Mammalian aging is characterized by the progressive loss of tissue integrity and function manifesting in ill health and increased risk for developing multiple chronic conditions. Accumulation of senescent cells in aging tissues partly contributes to this decline as targeted depletion of senescent cells in vivo ameliorates many age-related phenotypes. However, the fundamental molecular mechanisms responsible for the decline of cellular health and fitness during senescence and aging are largely unknown. In this study, we investigated whether chromatin-mediated loss of transcriptional fidelity, known to contribute to fitness and survival in yeast and worms, also occurs during human cellular senescence and mouse aging. Our findings reveal that aberrant transcription initiation inside genes is widespread in senescence and aging. It co-occurs with changes in the chromatin landscape and formation of non-canonical transcription start sites. Interventions that alter spurious transcripts have dramatic consequences on cellular health primarily affecting intracellular signal transduction pathways. We propose that spurious transcription is a conserved hallmark of aging that promotes a noisy transcriptome and a degradation of coherent transcriptional networks. Includes one replicate each of PRO-seq and three of PRO-CAP run-on transcription data from proliferating (PD20, PD23, PD26) and replicative senescent (PD67, PD76) fibroblasts.

哺乳动物机体衰老以组织完整性与功能进行性丧失为特征，表现为健康状况恶化，且罹患多种慢性疾病的风险升高。衰老组织中衰老细胞（senescent cells）的积累是该衰退过程的部分诱因，因为体内靶向清除衰老细胞可改善多种衰老相关表型。然而，细胞衰老与机体衰老过程中细胞健康及适应能力衰退的核心分子机制，目前仍大多尚未明确。本研究针对染色质介导的转录保真度丧失——该机制已被证实可影响酵母与线虫的适应能力及存活——是否同样存在于人类细胞衰老及小鼠机体衰老过程中展开了探究。本研究结果显示，基因内部的异常转录起始在细胞衰老与机体衰老过程中广泛存在，该现象与染色质表观景观的改变及非经典转录起始位点的形成同步发生。改变虚假转录本的干预手段会对细胞健康产生显著影响，主要作用于细胞内信号转导通路。我们提出，虚假转录是衰老的保守标志性特征，其可推动转录组产生噪声化效应，并破坏协调统一的转录调控网络。本数据集包含来自增殖态（PD20、PD23、PD26）及复制性衰老态（PD67、PD76）成纤维细胞的1组PRO-seq与3组PRO-CAP转录延伸测序重复数据。