Engineering epigenome editing tools: Current progress and future perspectives

Epigenome editing, the site-specific rewriting of chromatin modifications, provides a powerful approach to modulate gene regulation in basic research, biotechnology and pre-clinical settings. Synthetic epigenome editors (EpiEditors) contain a programmable DNA-binding module (CRISPR/dCas systems, zinc finger, and transcription activator-like effector proteins), combined with effector modules derived from chromatin-modifying enzymes (such as DNA methyltransferases or Ten-eleven translocation methylcytosine dioxygenases), or recruitment domains (such as Krüppel-associated box proteins). Substantial progress has been made in recent years in improving the specificity, stability, and functional robustness of epigenome editing technologies. Advances include optimized effector domains with reduced off-target activity, toxicity, and size, expanded CRISPR/Cas toolkits, combinatorial and modular editor designs, and increasingly efficient delivery strategies based on viral vectors, lipid nanoparticles, virus-like particles, and engineered exosomes. Epigenome editing allows the dissection of causal relationships between chromatin states and gene regulation, revealing context-dependent and combinatorial effects of epigenome modifications. Beyond basic research, a growing number of pre-clinical applications demonstrate durable repression or activation of disease-relevant genes in models of neurodegenerative disorders, imprinting diseases, cancer, and metabolic disorders such as hypercholesterolemia. These studies highlight both the therapeutic potential of epigenome editing and the importance of understanding chromatin context, downstream signaling, and cell type-dependencies. They also demonstrated the potential reversibility of the epigenome editing interrogation. Despite significant progress, key challenges remain, including the reliable prediction of editing outcomes, understanding the mechanistic basis of long-term stability, and the development of safe, efficient, and powerful delivery systems. Continued methodological development and systematic comparative studies are expected to further advance epigenome editing toward precision medicine applications.