Epigenetic and Epitranscriptomic Regulation of Mastitis in Dairy Cattle: A Review

Mastitis remains the most economically damaging disease in the global dairy industry, and conventional genetic selection based on somatic cell score (SCS) has produced only limited gains in resistance. Epigenetic mechanisms—mitotically heritable yet environmentally responsive and largely reversible modifications that regulate gene expression without altering the DNA sequence—are now emerging as a complementary layer of biological information that can sharpen the prediction of disease susceptibility. This review summarizes current evidence on three classes of epigenetic markers associated with bovine mastitis resistance: DNA methylation, non-coding RNAs (with emphasis on microRNAs, long non-coding RNAs, circular RNAs, and small nucleolar RNAs), and histone modifications, alongside the increasingly important epitranscriptomic layer of N6-methyladenosine (m6A) RNA modification. Particular attention is given to differentially methylated regions and discriminant methylation haplotype blocks in immune-related genes, circulating and milk-derived non-coding RNA biomarkers, m6A-mediated regulation of inflammatory transcripts, and histone-mark dynamics in mammary epithelial cells challenged with Staphylococcus aureus and Escherichia coli. We conclude with current limitations and perspectives on translating these markers into selection tools and therapeutic targets. Across all marker classes, current evidence remains constrained by small cohort sizes, breed-specific study designs, a scarcity of longitudinal and multi-generational data, and limited functional validation, so most candidate markers are still at the discovery stage and require cautious interpretation before deployment.