Network Biology led identification of critical miRNA modules for High Altitude hypoxia and their potential as dietary supplements
Abstract Early ascent to high altitude can cause severe damage to body functions and may lead to many fatal high-altitude disorders. To cope up with such conditions, the human body undergoes physiological and biochemical changes in order to adapt to extreme environmental conditions at high altitudes. Several microRNAs (miRNAs), Transcription Factors (TFs), and genes have been studied separately for their role in early adaptive molecular responses. We hypothesize that network analysis of miRNA-TF-gene co-regulatory networks of circulatory miRNAs (CmiRNAs) which are differentially expressed at high altitudes could reveal a complex regulatory functional module that might be controlling molecular adaptive responses at high altitude. A comprehensive and non-redundant list of differentially expressed human CmiRNAs during high altitude ascent was collated and 470 Feed-Forward Loops (FFLs) tripartite motifs were identified in the miRNA-TF-gene co-regulatory networks. Network analysis and K-means clustering identified 11 biologically overrepresented FFLs regulated by 8 miRNAs hsa-miR-335-5p, hsa-miR-26a-1-3p, hsa-miR-210-3p, hsa-miR-193b-3p, hsa-miR-17-5p, hsa-miR-16-5p, hsa-miR-5582-5p and hsa-miR-130a-3p. Pathway enrichment identified metabolism and inflammation as important hallmark responses responsible for high altitude adaptation. These miRNAs were evaluated for their supplementation from dietary sources. Phylogenetic analysis with 4 other mammalian and non-mammalian species showed that Bos taurus (cattle) milk could be a possible source of these dietary miRNAs. Exogenous miRNAs bta-mir-16-1, bta-mir-130a, bta-miR-335, and bta-miR-210 have >95% of sequence similarity and could become potential dietary miRNAs candidates. The sequence, structural properties, and high AGO2 binding efficiency of all these exogenous miRNAs show good serum stability and cellular uptake possibility in the mammalian host. Bta-miR-210 with highest Minimal Folding free Energy Index (MFEI) and highest Atomic Contact Energy (ACE) with AGO2 has the best potential to be a dietary supplement.