miRNA Proxy Hypothesis
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 ( 3, 4). Based on this work, we formulated the miRNA proxy hypothesis which states, “if a miR drives a specific biological phenotype…, the targets of that miR will drive the same biological phenotype. Thus, miRs can be used to identify (by proxy) the biological functions of specific glycosylation enzymes (or other proteins).”
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 have created a new high-throughput technology for validating miRNA:mRNA interactions, miRFluR (5). Using this technology, we are mapping miR regulation of the glycome and identifying new modes of miR regulation.
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4338-43. doi: 10.1073/pnas.1321524111.
- 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.
- 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.
- 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.
Thu, T.C.; Chung, J.Y.; Dhawan, D.; Vaiana, C.A.; Mahal, L.K. High-Throughput miRFluR Platform Identifies miRNA Regulating B3GLCT That Predict Peters’ Plus Syndrome Phenotype, Supporting the miRNA Proxy Hypothesis, ACS Chemical Biology, 2021, in Press, doi: 10.1021/acschembio.1c00247.