Epigenetic insights into fertility: involvement of immune cell methylation in dairy cows reproduction†

Infertility and post-partum reproductive diseases are significant challenges in cattle farming, with the maternal immune system's ability to recognize and tolerate the embryo being crucial for successful gestation. DNA methylation in hematopoietic cells may influence susceptibility to post-partum fertility issues, making the identification of epigenetic changes vital for sustainable animal production. This study aimed to characterize the methylome of immune cells in relation to fertility, potentially enabling early detection of subfertility. Using whole epigenome sequencing and enzymatic methyl-seq, we analyzed DNA methylation patterns in blood from twelve Holstein cows before the onset of any disease. Our findings revealed 216 990 differentially methylated cytosines (DMCs) between fertile and subfertile cows. Notably, three genes-Interferon tau-3 (IFNT3), KIAA0825, and RAS-Related Protein 2A-showed high significance in their differential methylation between fertile and subfertile cows. IFNT3, crucial for early embryonic development, had seven DMCs in its transcription start site (TSS) shores in subfertile cows. Additionally, the KLRA1 gene (Ly49), was identified as containing DMCs across all five genomic regions analyzed (TSS shores, exons, introns, downstream, and distal intergenic). Its widespread differential methylation highlights its potential impact on fertility. Key interleukin genes, including IL6, IL15, IL22, and IL36G, also showed multiple DMCs, reinforcing the role of the immune system in bovine fertility. These findings illustrate the potential control that immune cell epigenetics exert on cattle post-partum fertility. Additionally, this study suggests that the risk of developing subfertility could potentially be estimated with as few as 220 biomarkers, paving the way for enhanced animal health management and improved fertility treatments.