A hyper-quiescent chromatin state formed during aging is reversed by regeneration [ChIP-seq]

Epigenetic alterations are a key hallmark of aging but have not been extensively explored in tissues. Here, using naturally aged murine liver as a model and extending study 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 old cells show global H3K27me3-driven broad heterochromatinization and transcription suppression. At the local level, site-specific loss of H3K27me3 from promoters of genes encoding developmental transcription factors leads to expression in liver of non-hepatocyte markers. Interestingly, liver regeneration reverses H3K27me3 patterns and rejuvenates multiple molecular and physiological aspects of the aged liver. Overall design: ChIP-seq of H3K27me3 in 3 young and 3 old mouse livers, 4 young and 4 old mouse kidneys. ChIP-seq of 3 young and 3 old mouse livers before and after regeneration. ChIP-seq of EZH2 in 4 young and 4 old mouse livers. ChIP-seq of various histone modifications in 3-4 young (10-14 weeks) and 3-4 old (79-95 weeks) mouse tissues.