A hyper-quiescent chromatin state formed during aging is reversed by regeneration
Na Yang, James R. Occean, Daniël P. Melters, Changyou Shi, Lin Wang, Stephanie Stransky, Maı̀re E. Doyle, Chang‐Yi Cui, Michael Delannoy, Jinshui Fan, Eliza Slama, Josephine M. Egan, Supriyo De, Steven C. Cunningham, Rafael de Cabo, Simone Sidoli, Yamini Dalal, Payel Sen
Abstract
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.