An Overview of Programmable Epigenetic Editing Based on CRISPR Tools for Gene Expression Regulation

Epigenetic regulation provides a dynamic and reversible layer of gene control that functions independently of changes in DNA sequence, primarily mediated by DNA methylation, histone modifications, and higher-order chromatin organization. Aberrant epigenetic states contribute to a wide range of human diseases. However, conventional epigenetic therapies based on small-molecule inhibitors lack locus specificity and often cause global chromatin disturbances. The emergence of programmable epigenetic editing technologies has transformed the field by enabling targeted rewriting of chromatin states at defined genomic loci. Catalytically inactive CRISPR/Cas9 platforms fused to transcriptional activators, repressors, or chromatin-modifying enzymes now allow precise addition or removal of epigenetic marks without altering the underlying DNA sequence. This chapter provides an overview of the conceptual and technical foundations of CRISPR-based epigenetic editing, including tools for gene activation and repression, DNA methylation, histone modifications, and multiplexed systems that permit coordinated regulation of multiple genomic loci or epigenetic marks. Delivery methods for in vitro and in vivo applications are discussed, with an emphasis on viral and nonviral platforms that enable tissue-specific, durable gene regulation. Finally, recent preclinical and clinical studies highlight the potential of programmable epigenetic editing as a next-generation therapy for precise and reversible gene control.