Maternal undernutrition inhibits fetal rumen development： Novel miRNA-736-mediated dual targeting of E2F2 and MYBL2 in sheep

Background Undernutrition disrupts pregnant ewe’s metabolic homeostasis and severely inhibits fetal growth and development. In this study, undernourished and nutrition-recovery pregnant sheep models and rumen epithelial cells were utilized to investigate the mechanisms behind undernutrition-induced disruptions in fetal rumen metabolism and development. Results Maternal undernutrition significantly reduced fetal rumen weight and papilla length, width and surface area. Maternal undernutrition extremely suppressed nutrient metabolism and energy production in fetal rumen via JAK3 / STAT3 signaling to inhibit cell cycle progression and fetal rumen development, while maternal nutritional recovery partially restored metabolic inhibition but failed to alleviate fetal rumen development. Meanwhile, 64 differentially expressed miRNAs (DEMs) were identified in fetal rumen between undernourished ewes and controls. Novel miR-736 was overexpressed both in fetal rumen of undernourished and nutrition-recovery models. E2F transcription factor 2 ( E2F2 ) and MYB proto-oncogene like 2 ( MYBL2 ) were the intersection of fetal rumen differentially expressed genes (DEGs) and DEMs target genes integrated analysis and were predicted as miR-736 target genes. Further, we confirmed that miR-736 targeted and downregulated E2F2 and MYBL2 expressional levels. Silencing E2F2 and MYBL2 promoted apoptosis and inhibited S-phase entry in rumen epithelial cells. Conclusions In summary, maternal undernutrition disrupted fetal rumen metabolism and elevated miR-736, which targeted and downregulated E2F2 and MYBL2 to inhibit cell cycle progression and promote apoptosis, finally inhibited fetal rumen development. This study provides new insights into the epigenetic mechanisms underlying maternal undernutrition-induced fetal rumen developmental deficits.