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