DNA methylation hotspots reveal a critical window of susceptibility for growth and disease resilience in preweaning dairy calves

Results: A genome-wide epigenetic reconfiguration distinguishing resilient from susceptible animals was identified, comprising a 58-gene multi-phenotype core of convergent methylation signals. Deconvolution analysis confirmed that these signatures were independent of leukocyte composition, reflecting intrinsic cellular reprogramming rather than cell-type shifts. The methylomic landscape was dominated by hypermethylation of genes regulating neuronal and immune excitability (DPP6, CNTNAP2) and cytoskeletal dynamics (DIAPH3), suggesting a state of leukocyte activation and impaired migration.

Furthermore, metabolic sensors (PRKAG2) and barrier integrity genes (FRMD4A) emerged as dense methylation hotspots, linking growth impairment to a thrifty metabolic phenotype and compromised mucosal repair. Conclusions: These findings suggest that the preweaning window of susceptibility can act as an immune filter, leaving a stable epigenetic memory that constrains immune plasticity and metabolic allocation, thereby offering new targets for biomarkers in livestock health.