From epigenetic mark detection to rational design of epigenetic editing strategies.

Although cells within an organism share nearly identical genomes, their transcriptional programs differ markedly due to reversible chemical modifications known as epigenetic marks. These marks, including DNA methylation and histone modifications, regulate gene expression without altering DNA sequence and play a central role in development and disease. While epigenetic drugs such as DNA methyltransferase inhibitors have shown clinical benefit, their genome-wide activity often results in off-target toxicity limiting broader therapeutic applications. This has driven the development of locus-specific epigenetic editing strategies. Programmable epigenetic modifiers (PEMs) combine customizable DNA-binding platforms, such as CRISPR-dCas systems, transcription activator-like effectors (TALEs), or zinc fingers, with epigenetic effector domains to precisely install or remove regulatory marks at defined genomic loci. Because effective editing depends on the pre-existing epigenetic landscape, detection and characterization of target-site epigenetic states is a prerequisite for rational editor design, increasingly aided by machine-learning models that predict editing outcomes. In this review, we summarize current technologies for epigenetic mark detection and discuss the transition from global pharmacological approaches to programmable, modular editing systems that enable spatial and temporal control of gene regulation. We further address heritability and delivery constraints. Reversible, site-specific epigenetic editing represents a promising therapeutic paradigm for cancer, genetic disorders, and regenerative medicine.