Age-domains in Hyper-quiescent Cells Lead to Tissue Dysfunction

Taking a break from the hectic world now and again might just save your sanity; however, we sometimes need a push to get back up the pace of everyday life! Now, exciting new tissue rejuvenation-based research into the chromatin age-domains associated with hyper-quiescence suggests that aging cells also suffer from this pesky problem.

Aging tissues accumulate senescent cells, which have permanently stopped dividing; however, functional decline in tissues occurs before these cells appear. Quiescent cells – metabolically active and responsive but non-cycling – appear during the early stages of normal aging to support tissue function. Relatively relaxed researchers led by Payel Sen (National Institute on Aging, NIH) evaluated how epigenetic alterations associated with prolonged quiescence or “hyper-quiescence” impacted tissue function using the liver as a model, given its metabolic role, evidence of age-related decline, and regenerative capacity. Fascinatingly, they report that reversing the appearance of epigenetic “age-domains” in hyper-quiescent cells represents a means of reversing the age-related functional decline in tissues.

Let’s hear more from Yang and colleagues about how rejuvenated aged chromatin wakes cells from hyper-quiescence:

Integrated multi-omics and direct imaging revealed a paralog switching event in the enzymes catalyzing H3K27 methylation during liver cell hyper-quiescence that promotes a refractory cell state and compromises cell identity
- EZH2 expression decreases to prompt an age-related loss of H3K27me3 and EZH2 peaks at the promoters of developmental transcription factors genes and increased expression of non-hepatocyte markers
- EZH1 expression increases to prompt an age-related accumulation of H3K27me3 as megabase-scale heterochromatin gene-poor domains (“age-domains”) and global transcription suppression
H3K27me3-associated age-domains coincide with laminin-associated domains (LADs), which display H3K9me3 loss and H3K36me3, 5mC, and RNAPII depletion (already associated with senescence, aging, and premature aging diseases)
- Replacing H3K9me3 (constitutive) with H3K27me3 (facultative) heterochromatin may affect genome folding
Injury prompts aged hepatocytes to enter the cell cycle and repopulate the liver with new cells (liver regeneration)
- Limited proliferation abolishes differences in EZH1/2 expression, increases H3K27me3 at developmental genes to silence them, reduces the appearance of H3K27me3-associated age-domains, and corrects age-related transcriptomic changes

These findings suggest H3K27me3 as a mediator of liver aging and that analogous chromatin changes also occur in the kidney, heart, and muscle, where they may confer anti-tumor properties. This study also states that the proliferation-mediated global reduction in H3K27me3 levels could represent a strategy to ameliorate age-related decline and disease; indeed, the authors hypothesize that the benefits of Yamanaka factor-based reprogramming or parabiosis could derive from cell proliferation.

For more details about how to wake up aged cells from their hyper-quiescent snooze, see Molecular Cell, April 2023.