Editing without breaking: Sustained gene control via epigenetic rewriting

In the last 25 years, epigenetics has become a mature independent discipline, rooted in fundamental research in developmental biology and advancing toward clinical tools such as predictive epigenetic biomarkers and epigenetic drugs. Despite Food and Drug Administration (FDA)-approval, such epi-drugs suffer from genome-wide effects. Epigenetic editing, rewriting chromatin biochemical marks in a gene-targeted fashion, has received academic and commercial interest. Indeed, quickly upon the discovery of CRISPR-Cas9 as a flexible gene editing tool, rapid developments in gene-targeting technologies, including base editing and prime editing, have expanded the genome engineering toolbox. Importantly, this platform has also been repurposed for nuclease activity-free editing of gene states, enabling precise reprogramming of gene function rather than changing DNA sequences. Within the following decade, the gene-targeting field has achieved significant progress, with the first FDA-approved CRISPR-Cas9-based therapeutic and promising technologies going beyond wildtype Cas9. In this review, we discuss the state-of-the-art in epigenetic tools, including their therapeutic potential translating to clinical trials and current challenges.