Co-Expression Network and Integrative Analysis of Metabolome and Transcriptome Uncovers Biological Pathways for Fertility in Beef Heifers.

Reproductive failure remains a significant challenge to the beef industry. The omics technologies have provided opportunities to improve reproductive efficiency. We used a multistaged analysis from blood profiles to integrate metabolome (plasma) and transcriptome (peripheral white blood cells) in beef heifers. We used untargeted metabolomics and RNA-Seq paired data from six AI-pregnant (AI-P) and six nonpregnant (NP) Angus-Simmental crossbred heifers at artificial insemination (AI). Based on network co-expression analysis, we identified 17 and 37 hub genes in the AI-P and NP groups, respectively. Further, we identified TGM2 , TMEM51 , TAC3 , NDRG4 , and PDGFB as more connected in the NP heifers' network. The NP gene network showed a connectivity gain due to the rewiring of major regulators. The metabolomic analysis identified 18 and 15 hub metabolites in the AI-P and NP networks. Tryptophan and allantoic acid exhibited a connectivity gain in the NP and AI-P networks, respectively. The gene-metabolite integration identified tocopherol-a as positively correlated with ENSBTAG00000009943 in the AI-P group. Conversely, tocopherol-a was negatively correlated in the NP group with EXOSC2 , TRNAUIAP , and SNX12 . In the NP group, α-ketoglutarate- SMG8 and putrescine- HSD17B13 were positively correlated, whereas a-ketoglutarate- ALAS2 and tryptophan- MTMR1 were negatively correlated. These multiple interactions identified novel targets and pathways underlying fertility in bovines.