Extended Data Fig. 9: Hypothetical model of the epigenetic aging network.

The findings of this study indicate that epigenetic editing at age-hypermethylated CpGs, utilizing dCAS9-DNMT3A or CRISPRoff, leads to epigenetic bystander modifications that are notably enriched at other age-associated CpG sites—specifically, those CpGs that either gain or lose DNA methylation with aging. A similar phenomenon was observed when targeting hypomethylated CpGs. These bystander modifications appear to be concentrated in open chromatin regions within interacting chromatin domains. This suggests the existence of an epigenetic network in which differentially methylated regions can communicate with one another. Although the exact mechanism underlying this interaction remains unclear, such connections may contribute to the stabilization of the epigenetic state and facilitate coherent epigenetic modifications. At the single-cell level, we propose that age-associated DNAm is influenced not only by stochastic changes at individual CpGs but also by a genome-wide crosstalk of epigenetic modifications.