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miRNA proxy approach reveals hidden functions of glycosylation
- Kurcon, Tomasz, Liu, Zhongyin, Paradkar, Anika V., Vaiana, Christopher A., Koppolu, Sujeethraj, Agrawal, Praveen, Mahal, Lara K.
- Proceedings of the National Academy of Sciences of the United States of America 2015 v.112 no.23 pp. 7327-7332
- enzymes, glycosylation, messenger RNA, microRNA, non-coding RNA, polysaccharides, post-translational modification, regulatory sequences
- Glycosylation, the most abundant posttranslational modification, holds an unprecedented capacity for altering biological function. Our ability to harness glycosylation as a means to control biological systems is hampered by our inability to pinpoint the specific glycans and corresponding biosynthetic enzymes underlying a biological process. Herein we identify glycosylation enzymes acting as regulatory elements within a pathway using microRNA (miRNA) as a proxy. Leveraging the target network of the miRNA-200 family (miR-200f), regulators of epithelial-to-mesenchymal transition (EMT), we pinpoint genes encoding multiple promesenchymal glycosylation enzymes (glycogenes). We focus on three enzymes, beta-1,3-glucosyltransferase ( B3GLCT ), beta-galactoside alpha-2,3-sialyltransferase 5 ( ST3GAL5 ), and (alpha-N-acetyl-neuraminyl-2,3-beta-galactosyl-1,3)-N-acetylgalactosaminide alpha-2,6-sialyltransferase 5 ( ST6GALNAC5 ), encoding glycans that are difficult to analyze by traditional methods. Silencing these glycogenes phenocopied the effect of miR-200f, inducing mesenchymal-to-epithelial transition. In addition, all three are up-regulated in TGF-β–induced EMT, suggesting tight integration within the EMT-signaling network. Our work indicates that miRNA can act as a relatively simple proxy to decrypt which glycogenes, including those encoding difficult-to-analyze structures (e.g., proteoglycans, glycolipids), are functionally important in a biological pathway, setting the stage for the rapid identification of glycosylation enzymes driving disease states.