Transcription of endogenous retroviruses in pre-senescent cells contributes to the accumulation of double-stranded RNAs that trigger an anti-viral response that reinforces senescence. Transcription of endogenous retroviruses in pre-senescent cells contributes to the accumulation of double-stranded RNAs that trigger an anti-viral response that reinforces senescence

An important epigenetic switch marks the onset and maintenance of senescence. This allows transcription of the genetic programs that arrest the cell cycle and alter the microenvironment. Transcription of endogenous retroviruses (ERVs) is also a consequence of this epigenetic switch. In this manuscript, we have identified a group of ERVs that are epigenetically silenced in proliferating cells but are upregulated during replicative senescence or during various forms of oncogene-induced senescence, by RAS, Akt, or HDAC4 depletion. In an HDAC4 model of OIS, removal of the repressive histone mark H3K27me3 is the plausible mechanism that allows the transcription of intergenic ERVs during senescence. We have shown that ERVs contribute to the accumulation of dsRNAs in senescence, which can initiate the antiviral response via the IFIH1-MAVS signaling pathway and thus contribute to the maintenance of senescence. This pathway, and MAVS in particular, plays an active role in shaping the microenvironment and maintaining growth arrest, two essential features of the senescence program Overall design: Double strand RNA immunoprecipitation from proliferating SK-LMS-1 cells and cells undergoing senescence at 96h from HDAC4 depletion. Total RNA pre-immunoprecipitation was used as input

表观遗传开关是标记细胞衰老（senescence）起始与维持进程的关键调控节点。该开关可启动介导细胞周期阻滞与微环境重塑的遗传程序的转录。内源性逆转录病毒（endogenous retroviruses, ERVs）的转录亦是该表观遗传开关调控的产物。本研究中，我们鉴定出一类在增殖细胞中呈表观遗传沉默状态，但在复制性衰老，或经RAS激活、Akt激活或HDAC4敲低诱导的各类癌基因诱导衰老（oncogene-induced senescence, OIS）过程中被上调的ERVs。在HDAC4介导的OIS模型中，去除抑制性组蛋白修饰H3K27me3是衰老期间驱动基因间ERVs转录的潜在机制。我们证实，ERVs可促进衰老细胞中双链RNA（double-stranded RNA, dsRNAs）的积累，后者可通过IFIH1-MAVS信号通路激活抗病毒应答，进而参与衰老状态的维持。该信号通路，尤其是MAVS蛋白，在塑造衰老微环境、维持生长阻滞这两大衰老程序的核心特征中发挥关键调控作用。实验整体设计：分别从增殖态SK-LMS-1细胞，以及经HDAC4敲低诱导衰老96小时的细胞中开展双链RNA免疫沉淀实验；免疫沉淀前的总RNA作为输入对照样本。