Beyond DNA—CRISPR technologies for epigenome editing and transcriptional regulation in disease: A scoping review
Elijah Kolawole Oladipo, Victoria Oluwayemisi Adubiaran, Aanuoluwa Temitayo Iyiola, Biobele Winner Sokari, Ummulkhairi Tukur, Nimah Adejoke Adeoye, Augusta Edet Udo, Ifeoma Vivian Anyia, Juwaretu Ahuoiza Musa, Elibe Patricia, Edikan Umoh, Hezekiah Oluwajoba Awobiyi, Oluwanifemi Omodara Ogunleye, Gospel Ndunaka, Oluwaseyi Samuel Akinpelu, Helen OnyeakaAbstract
Background
CRISPR‐derived epigenome editors enable locus‐specific control of gene expression without changing the underlying DNA sequence, creating therapeutic opportunities for dosage‐sensitive disorders, imprinting diseases, aberrant gene activation and reversible cell‐state engineering.
Main body
This scoping review maps mechanistic classes, target‐validation strategies, emerging platforms, translational evidence and unresolved risks of CRISPR‐based epigenome editing. A structured PubMed/MEDLINE search and citation‐chain review were updated in July 2026, with a targeted update of recent peer‐reviewed literature before revision. The field has progressed from CRISPR interference (CRISPRi) and activation to direct rewriting of DNA methylation and histone marks, programmable transcriptional memory, compact effectors, transient ribonucleoprotein or mRNA delivery, and externally controllable systems. Preclinical studies demonstrate correction of dosage‐sensitive and imprinting phenotypes, programmable regulation in human neurons and primary immune cells, and durable in vivo silencing after transient delivery. Target selection nevertheless requires orthogonal validation: nuclease knockout, conditional loss‐of‐function, CRISPRi, rescue, and reverse‐editing experiments answer different biological questions and should be interpreted together when establishing causality. The absence of DNA cleavage does not make epigenome editing intrinsically risk free. Development must address seed‐sequence‐mediated off‐target regulation, chromatin spreading, allele and cell‐type specificity, persistence, immune responses, delivery constraints and uncertainty regarding the relationship between a molecular epigenetic change and clinical phenotype.
CONCLUSION
CRISPR epigenome editing is approaching clinical translation, but adoption will depend on rigorous causal target validation, standardized reporting, multilayer specificity assays, controllable delivery and evidence that corrected expression remains within a safe physiological window.