Potential of Micronuclear Epigenetic Signatures in Analyses of Toxicity and Genomic Instability

Micronuclei (MN) are small extranuclear chromosomal fragments that arise from genomic instability and serve as established biomarkers for genotoxicity and disease susceptibility. Once considered only markers of disease, they are now recognized as active, causative drivers of disease progression, driven by emerging evidence of epigenetic regulation within these structures. The micronucleus assay is recognized as a cost-effective and minimally invasive method for monitoring genotoxicity resulting from both chronic and early exposure to environmental factors such as arsenic and lead, as well as from genetic instability associated with cancer progression. This review critically examines the expanding role of MN beyond traditional cytogenetic endpoints, with particular emphasis on recent insights into their epigenetic landscape. Mass spectrometry-based studies have demonstrated that MN possess distinct histone posttranslational modification signatures compared to primary nuclei, including alterations in H3K27ac, H3K9ac, and H3K18ac. These modifications affect chromatin structure, gene expression, and DNA repair mechanisms. In the context of xenobiotic exposures, MN-associated epigenetic changes may function as early indicators of disease progression. Additionally, rupture of the MN envelope can activate innate immune responses through the cGAS-STING pathway or result in chromothripsis, both of which contribute to cancer progression. The concept of "Micronuclear Epigenetics" is highlighted, with its potential application in high-throughput diagnostic platforms, particularly liquid biopsy, discussed. This approach may enhance early detection and risk stratification in exposure-induced toxicity and diseases such as cancer.