Mammalian cellular identity erodes with age through predictable chromatin drift

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.