The role of R-loops-mediated epigenetic regulation in genome stability maintenance and disease pathogenesis: a systematic review.

Clinical Snapshot

Key Findings

• Effect Size: Not applicable - qualitative synthesis

• Primary Outcome: R-loops serve as intermediates linking transcription, chromatin regulation, and genome maintenance

• Nnt Or Sensitivity: Context-dependent effects with disease-, locus-, and cell-state specificity

• Confidence Interval: Not reported

Clinical Application

Currently limited to research applications; clinical translation requires further development Relevant to Australian genomic medicine initiatives and precision oncology programs; potential future applications in TGA-regulated diagnostic development Patients with epigenetic disorders, cancer, and genome instability syndromes

Abstract

This systematic review synthesizes current evidence linking R-loops - associated processes with epigenetic regulation, genome stability, and human disease, integrating findings across DNA/RNA/protein modifications and 3D genome organization, and highlighting key mechanistic and technical gaps relevant to future studies, including longer-term translational exploration. Following PRISMA guidelines (Registration No.: INPLASY202560055), PubMed and ScienceDirect databases were searched through 18 January 2026. Two independent reviewers conducted blinded screening via the Rayyan platform. From 1290 initial articles, 71 studies met inclusion criteria. Methodological rigour was assessed using a modified SYRCLE risk-of-bias tool. Thematic synthesis identifies R-loops as recurrent intermediates linking transcription, chromatin regulation, and genome maintenance; feedback-like relationships are reported in selected systems. They spatially impede DNMTs to sustain promoter hypomethylation while recruiting TET enzymes for demethylation, and RNA modifications (e.g. m5C/m6A) may tune hybrid stability and, in some contexts, influence effector recruitment. R-loops facilitate the recruitment of histone-modifying complexes (PRC1/PRC2, G9a/GLP), thereby influencing chromatin landscapes and 3D genome architecture - including associations with TAD boundary insulation and with LLPS-related repair compartments in specific contexts. Dysregulation of R-loop homeostasis links to disease-related epigenetic alterations and genome instability with distinct disease-, locus- and cell-state specificity, and its context-dependent roles in diverse disorders involve transcriptional silencing, DNA damage, replication-transcription conflicts, repair pathways, chromatin regulation and mitochondrial genome maintenance. Integrating DRIP-seq with epigenomic profiling and functional tests supports mapping of context-specific relationships.

References

1. 1.Jiang, Z. H., Wang, D. F., Shao, R., Wang, X. S., & Tang, Z. R. (2026). The role of R-loops-mediated epigenetic regulation in genome stability maintenance and disease pathogenesis: a systematic review. Epigenetics. https://doi.org/10.1080/15592294.2026.2653959