Multi-omics integration identifies regulatory factors underlying bovine subclinical mastitis

AbstractBackground Mastitis caused by multiple factors remains one of the most common and costly disease of the dairy industry. Multi-omics approaches enable the comprehensive investigation of the complex interactions between multiple layers of information to provide a more holistic view of disease pathogenesis. Therefore, this study investigated the genomic and epigenomic signatures and the possible regulatory mechanisms underlying subclinical mastitis by integrating RNA sequencing data (mRNA and lncRNA), small RNA sequencing data (miRNA) and DNA methylation sequencing data of milk somatic cells from ten healthy cows and twenty cows with naturally occurring subclinical mastitis caused byStaphylococcus aureusorStaphylococcus chromogenes. Results Functional investigation of the data sets through gene sets analysis uncovered 3458 biological process GO terms and 170 KEGG pathways with altered activities during subclinical mastitis, providing further insights into subclinical mastitis and revealing the involvement of multi-omics signatures in the altered immune responses and impaired mammary gland productivity during subclinical mastitis. The abundant genomic and epigenomic signatures with significant alterations related to subclinical mastitis were observed, including 30,846, 2552, 1276 and 57 differential MHBs (dMHBs), differentially expressed genes (DEGs), lncRNAs (DELs) and miRNAs (DEMs), respectively. Next, five Factors presenting the principal variation of differential multi-omics signatures were identified. The important roles of Factors 1 and Factor 2 in the regulation of immune defense and impaired mammary gland functions during subclinical mastitis were revealed. Also, networks of important functional gene sets with the involvement of multi-OMICs signatures were demonstrated, which contributed to a comprehensive view of the possible regulatory mechanisms underlying subclinical mastitis. Furthermore, multi-omics integration enabled the association of the epigenomic regulatory factors of altered genes in important pathways, such as ‘Staphylococcus aureusinfection pathway’ and ‘natural killer cell mediated cytotoxicity pathway’, etc., which provides further insights into mastitis regulatory mechanisms. Moreover, few multi-omics signatures (14 dMHBs, 25 DEGs, 18 DELs and 5 DEMs) were identified as candidate discriminant signatures with capacity of distinguishing subclinical mastitis cows from healthy cows. Conclusion The integration of genomic and epigenomic data by multi-omics approaches in this study provided a better understanding of the molecular mechanisms underlying subclinical mastitis and identified multi-omics candidate discriminant signatures for subclinical mastitis, which may ultimately lead to the development of more effective mastitis control and management strategies.