A hyper-quiescent chromatin state formed during aging is reversed by regeneration

Yang, N.; Occean, J. R.; Melters, D. P.; Shi, C.; Wang, L.; Stransky, S.; Doyle, M. E.; Cui, C.-Y.; Delannoy, M.; Fan, J.; Slama, E.; Egan, J. M.; De, S.; Cunningham, S. C.; Cabo, R. d.; Sidoli, S.; Dalal, Y.; Sen, P.

doi:10.1101/2023.02.14.528512

bioRxiv · 10.1101/2023.02.14.528512

A hyper-quiescent chromatin state formed during aging is reversed by regeneration

Yang, N.·Occean, J. R.·Melters, D. P.·Shi, C.·Wang, L.·Stransky, S.·Doyle, M. E.·Cui, C.-Y.·Delannoy, M.·Fan, J.·Slama, E.·Egan, J. M.·De, S.·Cunningham, S. C.·Cabo, R. d.·Sidoli, S.·Dalal, Y.·Sen, P.

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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 transcription 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.

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Yang, N., Occean, J. R., Melters, D. P., Shi, C., Wang, L., Stransky, S., Doyle, M. E., Cui, C.-Y., Delannoy, M., Fan, J., Slama, E., Egan, J. M., De, S., Cunningham, S. C., Cabo, R. d., Sidoli, S., Dalal, Y., Sen, P.. 2023-02-15. A hyper-quiescent chromatin state formed during aging is reversed by regeneration. https://doi.org/10.1101/2023.02.14.528512

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