Epigenetic Memory in Human Diseases: Acquired Chromatin States as Targetable Drivers of Disease Evolution

Clinical heterogeneity remains a major challenge across human diseases, where patients with similar genetic backgrounds frequently exhibit striking differences in disease progression, therapeutic response and clinical outcome. Increasing evidence indicates that these differences cannot be explained by genetic variation alone, positioning epigenetic memory as a critical non-genetic determinant of disease behavior. Epigenetic memory refers to the stable yet reversible propagation of transcriptional states through mechanisms including DNA methylation, histone modifications, chromatin accessibility, enhancer dynamics and higher-order chromatin organization. In this review, we synthesize emerging mechanistic and translational evidence demonstrating how epigenetic memory integrates environmental, metabolic, inflammatory, infectious and therapeutic cues into persistent cellular programs that drive inter-patient, intra-tumoral and temporal heterogeneity. We discuss its disease-specific manifestations across cancer, immunological, neurological, and metabolic disorders, with particular emphasis on cellular plasticity, stemness, immune evasion, drug-tolerant persister states and relapse. Furthermore, we highlight recent advances in single-cell and spatial epigenomics, liquid-biopsy-based epigenetic biomarkers, CRISPR-mediated epigenome editing and targeted chromatin therapies that collectively establish epigenetic memory as both a measurable biomarker and a therapeutically actionable vulnerability. By framing epigenetic memory as a dynamic interface between genome and environment, this review provides a unified conceptual framework for understanding disease evolution and advancing precision epigenetic medicine.