Insight the role of human endogenous retroviruses (HERVs) in senescence

The epigenome of senescent cells is characterized by widespread epigenetic rearrangements. The epigenetic changes play a dual role in the execution of the senescence program by promoting permanent growth arrest and altering the cellular microenvironment through the senescence-associated secretory phenotype (SASP). Epigenome rewiring in senescent cells is characterized by a profound redistribution of H3K27ac/H3K27me3 marks. Class IIa histone deacetylases (HDAC4, 5, 7, 9) monitor H3K27 acetylation status as part of a large epigenetic multiprotein complex. We have previously established that HDAC4 plays a central role in regulating the senescence program. During senescence, HDAC4 is degraded by the proteasome, and its levels are also reduced in the skin and liver of aged mice. Artificial deletion of HDAC4 in transformed cell lines triggers senescence. The onset of senescence is achieved by activation of enhancers and super-enhancers that monitor the senescence program (Di Giorgio et al 2021). During senescence, epigenetic perturbations also trigger the transcription of human endogenous retroviruses (HERVs), a class of RNA retrotransposons that contain a long terminal repeat (LTR). HERVs are normally silenced by epigenetic mechanisms acting on DNA (CpG methylation) and chromatin (histone methylation). Once expressed, HERV transcripts mainly fold into dsRNA structures and activate a family of cytoplasmic RNA sensors of the innate immune system. Activation of these sensors leads to proliferation arrest, senescence, and apoptosis. DNA hypomethylating agents and HDACs inhibitors promote HERVs derepression in various cancer cell lines. In this PhD thesis, we observed increased expression of some HERVs in different models of senescence. Their upregulation correlates mainly with an apparent H3K27me3 demethylation, achieved after knockout of HDAC4. The group of HERVs upregulated during senescence is not induced in response to genome instability. The accumulation of HERVs in the cytoplasm triggers the activation of the IFN response. Similarly, exogenous administration of dsRNAs immunopurified from HDAC4 -/- cells or transfection of poly (I:C), synthetic molecules that mimic dsRNAs, activate the IFN response. dsRNAs can also trigger senescence and cell death in low-grade sarcoma cells and in normal fibroblasts. We suggest that the depletion of HDAC4 promotes the development of an inflammatory state, directly through activation of enhancers and super-enhancers that monitor SASP gene expression, and indirectly through derepression of HERVs and a consequent activation of the IFN response. Overall, this PhD thesis opens the way to further investigation aimed to understand whether the activation of HERVs during senescence and aging is not limited to the regulation of the immune microenvironment but also to the maintenance of senescent status.