Mammalian cellular identity erodes with age through predictable chromatin drift
Imperfect maintenance of developmental chromatin constraints causes age-associated DNA methylation gains predominantly at polycomb-regulated genomic regions across mammalian tissues.
Nature · 30 Sept · Yücel AD, Molière A, Gladyshev VN
In mammalian cells, development establishes a regulatory chromatin grammar that progressively erodes during aging, driving the loss of cellular identity. Researchers developed a framework extending Waddington's epigenetic landscape to explain this decanalization process. During development, globally coordinated chromatin programs establish identity constraints across multiple timescales. Adult tissues subsequently rely on local mechanisms that maintain these constraints with imperfect fidelity, producing predictable drift over biological time. Antagonistic chromatin pathways, specifically polycomb repressive complex 2 (PRC2) repression balanced by H3K4/36 methylation and RNA polymerase II binding, enforce identity boundaries. With age, this balance deteriorates. In somatic mitotic tissues, the vast majority of age-associated DNA methylation gains concentrate at PRC2-bound low-methylated regions, marking these sites as conserved coordinates of slow epigenetic drift.
Why it matters
This model explains cross-tissue aging signatures, developmental timing correlations with lifespan, and the broad robustness of pan-mammalian epigenetic aging clocks. It highlights how stabilizing chromatin architecture could potentially preserve cellular identity and function over time.
Caveats
The findings represent a theoretical and computational framework rather than direct experimental interventions. Functional validation is required to test whether manipulating these specific chromatin boundaries can preserve cell identity in living organisms.
The paper
Written in development and lost in ageing: the grammar of cellular identity
Yücel AD, Molière A, Gladyshev VN
Nature
doi.org/10.1038/s41586-026-10955-0