Heat-stress-induced DNA methylation remodeling in cattle: a systematic evidence synthesis and meta-analytic...

Heat stress is an increasingly important constraint on cattle welfare, fertility, productivity, and developmental resilience. DNA methylation may mediate part of the molecular response to thermal exposure, but current studies differ widely in tissue type, exposure model, assay platform, and endpoint definition. This review systematically synthesizes evidence linking heat stress to DNA methylation changes in cattle and evaluates whether a quantitative meta-analysis of global methylation responses is currently feasible. A PRISMA-informed search was conducted for peer-reviewed bovine studies published between 2015 and early 2026. The PECO framework defined cattle or cattle-derived biological material as the population, heat stress or thermal challenge as the exposure, thermoneutral, cooled, or non-stressed conditions as comparators, and DNA methylation-related measures as outcomes. The predefined primary quantitative endpoint was global DNA methylation or hydroxymethylation reported as a continuous outcome. Locus-specific, promoter-level, DMC, DMR, and multi-omics studies were retained for structured qualitative synthesis. Global methylation studies often reported non-significant bulk changes, whereas sequencing-based and promoter-level studies revealed extensive tissue-specific and locus-specific methylation signatures involving oxidative stress, immune regulation, metabolism, endocrine signaling, and developmental programming. A formal pooled meta-analysis was not statistically defensible because fewer than three independent studies reported complete and comparable group-level data for the predefined global methylation endpoint. Heat stress in cattle appears to induce targeted, tissue-specific methylome remodeling rather than a consistent genome-wide shift in global methylation. Future studies should report extractable group-level methylation statistics, standardized heat-load metrics, tissue and cell-composition information, and phenotypic outcomes to enable robust meta-analysis. Beyond reporting standardization, future trial and cohort designs should prospectively incorporate paired global and locus-specific methylation endpoints to enable meta-analytic pooling within the next research cycle.