HDAC4 controls senescence and aging by safeguarding the epigenetic identity and ensuring the genomic integrity

The epigenome of senescent cells is characterized by a deep redistribution of H3K27 acetylation. H3K27 is target of class IIa Histone Deacetylases (HDAC4, 5, 7, 9) as part of large repressive complexes. We report here that, among class IIa HDACs, HDAC4 is post-transcriptionally downregulated during senescence and aging. HDAC4 knock-out (KO) triggers premature senescence as a result of two waves of biological events: the accumulation of replication stress (RS) and the expression of inflammatory genes. The latter is achieved directly, through the activation of enhancers (TEs) and super-enhancers (SEs) that are normally monitored by HDAC4, and indirectly, through the de-repression of repetitive elements of retroviral origin (ERVs). The accumulation of DNA damage and the activation of the inflammatory signature influence each other and integrate into a synergistic response required for senescence onset. Our work discloses the key role played by HDAC4 in maintaining epigenome identity and genome integrity.