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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.