MicroRNA-coordinated synergism for placental gene regulation throughout pregnancy

The regulation of gene expression by microRNAs (miRNAs) is essential during development. However, it is necessary to move beyond individual miRNAs to understand their functions and the intricate interplay as a coordinated system. To address this, we developed and implemented a network approach named miRNA-gene synergic co-regulatory networks. This method builds networks identifying pairs of genes jointly regulated (co-regulation) by multiple miRNAs (synergism). Using these networks, focusing on placental genes, we evaluated the coordinated regulation of miRNAs from different origins (maternal circulating extracellular vesicles (EVs) or placental tissue) and at different times (increased expression in the first or third trimester of pregnancy) using both public and original data. We observed that synergic co-regulatory networks displayed properties compatible with scale-free topology. When comparing the co-regulation networks produced by miRNAs differentially expressed at distinct gestational periods, we identified that miRNAs from the maternal circulation were more coordinated at the first trimester, while the miRNAs from the placental tissue were more coordinated at the third trimester. Regarding maternal circulating miRNAs in the first trimester, we identified a co-expression module that was negatively associated with birth weight. This module, together with other miRNAs expressed at higher levels in the first trimester, regulates transforming growth factor beta (TGF-β) signaling pathways that are important for uteroplacental circulatory development. Overall, the results of this study reinforce the idea that miRNAs, whether associated with EVs in maternal circulation or derived from placental tissue, constitute a regulatory system with dynamic coordination throughout pregnancy.