Epigenetic basis for the establishment of ruminal tissue-specific functions in bovine fetuses and adults.

Epigenetic regulation in the rumen, a unique ruminant organ, remains largely unexplored compared with other tissues studied in model species. In this study, we perform an in-depth analysis of the epigenetic and transcriptional landscapes across fetal and adult bovine tissues as well as pluripotent stem cells. Among the extensive methylation differences across various stages and tissues, we identify tissue-specific differentially methylated regions (tsDMRs) unique to the rumen, which are crucial for regulating epithelial development and energy metabolism. These tsDMRs cluster within super-enhancer regions that overlap with transcription factor (TF) binding sites. Regression models indicate that DNA methylation, along with H3K27me3 and H3K27ac, can be used to predict enhancer activity. Key upstream TFs, including SOX2, FOSL1/2, and SMAD2/3, primarily maintain an inhibitory state through bivalent modifications during fetal development. Downstream functional genes are maintained mainly in a stable repressive state via DNA methylation until differentiation is complete. Our study underscores the critical role of tsDMRs in regulating distal components of rumen morphology and function, providing key insights into the epigenetic regulatory mechanisms that may influence bovine production traits.