miRNA Proxy Approach
MicroRNAs (miRs) are small, non-coding RNAs that regulate the translation and stability of mRNA transcripts, primarily via interactions with their 3’-untranslated regions (3’UTRs). MiRs act as rheostats, tuning the protein expression of key genes within a biological network. Inhibition of miR-targeted genes typically mimics the biological effects associated with the miRs, thus miRs are natural seekers of proteins whose expression shifts the network from one biological state to another. Recently, we have shown glycosylation is a major target of miR-based regulation (1, 2) and that miR regulation can be used to identify changes in the protein expression of glycosylation genes (glycogenes) that drive specific biological processes (miRNA proxy approach, 3, 4). Currently our laboratory is working on extending our miRNA proxy approach to predict glycosylation changes driving biological changes (e.g. melanoma metastasis, pathogen response) using multi-miR networks. To this end we are creating new high-throughput technology for validating miRNA:mRNA interactions and incorporating miRNA interactions into our systems-based models of glycomic changes.
Fig. 1. miRNA proxy approach as applied to glycome: miRNA can be used to identify glycosylation enzymes and theircorresponding glycans that drive disease states.
1. Agrawal, P.; Kurcon, T.; Pilobello, K.T.; Rakus, J.F.; Koppolu, S.; Liu, Z.; Batista, B.S.; Eng, W.S., Hsu, K.-L.; Liang, Y.; Mahal, L.K. Mapping posttranscriptional regulation of the human glycome uncovers microRNA defining the glycocode. Proc. Natl. Acad. Sci., USA, 2014, 111,
4338-43. doi: 10.1073/pnas.1321524111.
2. Kasper, B.T.; Koppolu, S.; Mahal, L.K. Insights into MiRNA Regulation of the Human Glycome. Biochem. Biophys. Res. Commun. 2014, 445, 774-9. doi: 10.1016/j.bbrc.2014.01.034.
3. Kurcon, T.; Liu, Z.; Paradkar, A.V.; Vaiana, C.A.; Koppolu, S.; Agrawal, P.; Mahal, L.K. miRNA proxy approach reveals hidden functions of glycosylation. Proc. Natl. Acad. Sci., USA, 2015, 112, 7327-32. doi: 10.1073/pnas.1502076112.
4. Vaiana, C.A.; Kurcon, T.; Mahal, L.K. MicroRNA-424 Predicts a Role for β-1,4 Branched Glycosylation in Cell Cycle Progression. J. Biol. Chem., 2016, 291, 1529-37. doi: 10.1074/jbc.M115.672220.