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Epigenetic alterations are a key hallmark of aging but have been limitedly explored in tissues. Here, using naturally aged murine liver as a model and extending to other quiescent tissues, we find that aging is driven by temporal chromatin alterations that promote a refractory cellular state and compromise cellular identity. Using an integrated multi-omics approach and the first direct visualization of aged chromatin, we find that globally, old cells show H3K27me3-driven broad heterochromatinization and transcriptional suppression. At the local level, site-specific loss of H3K27me3 over promoters of genes encoding developmental transcription factors leads to expression of otherwise non-hepatocyte markers. Interestingly, liver regeneration reverses H3K27me3 patterns and rejuvenates multiple molecular and physiological aspects of the aged liver. [Display omitted] • Global increase of H3K27me3 is a common signature of aged liver and other tissues • H3K27me3 is lost at peak regions and gained at lamin-associated domains • Liver regeneration reverses age-related H3K27me3 and transcriptomic patterns Yang et al. find that the histone modification H3K27me3 accumulates in many tissues with age, due to increased time in quiescence. H3K27me3 is gained over lamin-associated domains but reduced at developmental gene promoters with consequent changes in global and local transcription. Liver regeneration breaks quiescence and partially restores youthful patterns. [ABSTRACT FROM AUTHOR]