Learning Principle for the Adaptive Shaping of Epigenetic Memory Repertoires

Biological systems maintain long-term memories that guide future behavior but face the challenge of retaining beneficial memories while eliminating harmful ones. This challenge is exemplified in gene silencing mechanisms, which must suppress deleterious genetic elements without affecting essential genes. These systems face a fundamental credit assignment problem, as the fitness consequences of individual memory units are revealed only through aggregate physiological outcomes such as cellular growth or DNA damage. We propose that eukaryotic gene silencing mechanisms address this challenge through fluctuation-driven feedback. Silenced genomic regions are memory units whose stability depends on fluctuating residual transcription, and different genomic regions are coupled through shared epigenetic modifiers that respond to global stress signals. Our analysis shows that this feedback loop preferentially stabilizes the silencing of harmful elements, enabling adaptive refinement of the memory repertoire over time. The model explains the paradoxical reliance of stable silencing on residual transcription and the adaptive role of stress-induced desilencing, makes specific testable predictions, and illustrates how fluctuation-driven feedback can shape memory repertoires in biological systems.