Next generation technologies for CRISPR-based epigenome and transcriptional modulation

Technologies for editing epigenetic modifications and controlling transcription in mammalian cells have revolutionized targeted gene perturbation, functional genomics, and basic research. By avoiding the generation of DNA breaks, epigenome editing serves as a safe and precise approach for altering gene expression and has emerged as a promising platform for therapeutic applications. The advent of CRISPR has contributed significantly to the expansion of the existing toolkit for programmable modulation of epigenetic and transcriptional states. This review highlights recent discoveries in engineering novel tools for epigenome editing and transcriptional modulation through rational design, high throughput screening methods, and mutational scans, which leverage the endogenous reservoir of chromatin and transcriptional effectors for targeted gene repression and activation. We also discuss the therapeutic potential of epigenome modulators and highlight the key challenges that need to be addressed to improve their safety and efficacy. Advancing our understanding of the complex mechanisms driving gene expression and overcoming current limitations will pave the way for the development of novel technologies that advance fundamental research and translational applications.