CRISPR-epigenetic crosstalk: From bidirectional regulation to therapeutic potential

Recent advances in epigenetics have elucidated the pivotal roles of epigenetic modifications in genomic regulation and disease pathogenesis. Concurrently, CRISPR-based technologies have transcended conventional gene-editing applications and have emerged as powerful tools for target gene screening, chromatin imaging, and epigenetic modulation. Notably, epigenetic landscapes substantially influence the CRISPR editing efficiency, whereas CRISPR itself can reshape epigenetic states, forming a dynamic CRISPR-Epigenetics Regulatory Circuit. This review systematically examines the bidirectional interplay between CRISPR systems and epigenetic modifications, emphasizing their collective impact on genome-editing precision, disease progression, and therapeutic development. Existing studies have predominantly focused on the application of CRISPR in epigenetic modifications or the impact of epigenetic landscapes on CRISPR, exhibiting unidirectional characteristics. However, accumulating evidence suggests a bidirectional interaction between the two. Here, a transformative "CRISPR-Epigenetics Regulatory Circuit" model is synthesized and presented, supported by three pivotal breakthroughs: demonstrating CRISPR as an active epigenetic programmer, synthesizing the epigenetic preconditioning therapeutic paradigm, and elucidating the first predictive mathematical model (EPIGuide). Further exploration of this circuit is expected to enhance CRISPR performance, optimize sgRNA design via epigenetic predictive models, and pioneer sequential epigenetic or gene editing therapies.