Department of Laboratory Medicine and Pathology, University of Washington, Seattle, WA 98195, USA.
Systemic Autoimmune Diseases Research Unit, Vall d’Hebron Research Institute (VHIR), Barcelona 08035, Spain.
Aging (Albany NY). 2023 May 22;15(10):4012-4034. doi: 10.18632/aging.204743.
Cellular senescence is a dynamic stress response process that contributes to aging. From initiation to maintenance, senescent cells continuously undergo complex molecular changes and develop an altered transcriptome. Understanding how the molecular architecture of these cells evolve to sustain their non-proliferative state will open new therapeutic avenues to alleviate or delay the consequences of aging. Seeking to understand these molecular changes, we studied the transcriptomic profiles of endothelial replication-induced senescence and senescence induced by the inflammatory cytokine, TNF-α. We previously reported gene expressional pattern, pathways, and the mechanisms associated with upregulated genes during TNF-α induced senescence. Here, we extend our work and find downregulated gene signatures of both replicative and TNF-α senescence were highly overlapped, involving the decreased expression of several genes associated with cell cycle regulation, DNA replication, recombination, repair, chromatin structure, cellular assembly, and organization. We identified multiple targets of p53/p16-RB-E2F-DREAM that are essential for proliferation, mitotic progression, resolving DNA damage, maintaining chromatin integrity, and DNA synthesis that were repressed in senescent cells. We show that repression of multiple target genes in the p53/p16-RB-E2F-DREAM pathway collectively contributes to the stability of the senescent arrest. Our findings show that the regulatory connection between DREAM and cellular senescence may play a potential role in the aging process.
细胞衰老（cellular senescence）是一种有助于衰老的动态应激反应过程。从起始到维持，衰老细胞不断经历复杂的分子变化，并发展出改变的转录组（transcriptome）。了解这些细胞的分子结构如何演变以维持其非增殖状态，将为缓解或延迟衰老的后果开辟新的治疗途径。为了理解这些分子变化，我们研究了内皮细胞复制诱导衰老和炎症细胞因子 TNF-α诱导衰老的转录组谱。我们之前报告了与 TNF-α诱导衰老过程中上调基因相关的基因表达模式、途径和机制。在这里，我们扩展了我们的工作，并发现复制诱导和 TNF-α 诱导衰老的下调基因特征高度重叠，涉及几个与细胞周期调控、DNA 复制、重组、修复、染色质结构、细胞组装和组织相关的基因表达降低。我们确定了多个 p53/p16-RB-E2F-DREAM 的靶点，这些靶点对于增殖、有丝分裂进展、解决 DNA 损伤、维持染色质完整性和 DNA 合成至关重要，而这些靶点在衰老细胞中受到抑制。我们表明，p53/p16-RB-E2F-DREAM 通路中多个靶基因的抑制共同导致衰老停滞的稳定性。我们的发现表明，DREAM 与细胞衰老之间的调控联系可能在衰老过程中发挥潜在作用。
