Dynamical Regimes in Rejuvenation

Abstract

Biological aging is accompanied by systematic changes in epigenetic modifications and chromatin organization. The reversal of the effects of aging, rejuvenation, is experimentally achieved by the transient induction of factors that modify these marks in cells and organisms. Here, we show that key features of rejuvenation experiments emerge from the biophysical interplay between dynamic epigenetic marks and the three-dimensional conformation of chromatin. Using a minimal field theory and molecular dynamics simulations, we show that the system responds in three distinct temporal regimes. The intermediary regime fulfills necessary conditions for successful rejuvenation. In this regime, the system spends time near a separatrix, allowing for high epigenetic plasticity, while memory retained in the chromatin conformation enables restoration of the original epigenetic correlations. Analysis of sequencing data further supports the predicted coupling between chromatin compaction and epigenetic correlations. Our results provide a physical explanation for how rejuvenation may remodel age-associated epigenetic states without irreversibly erasing cellular identity. We identify a general mechanism by which memory stored in a slow structural variable permits reversible remodeling of a faster internal state.