When following tortuous and intertwined biomolecular pathways, one can easily lose one’s way. Especially disorienting are the pathways through the dense glycome, where the steps that lead to glycosylation—the glycogenes, glycosylation enzymes, and glycans—can be obscured by the biochemical undergrowth and detritus. Rather than scanning the landscape, trying to pick out the glycosylation trail, however, it may be easier to spot convenient trail blazes, which in this case may consist of microRNAs.
MicroRNAs, or miRNAs, are regulatory molecules that spur changes in a cell by inhibiting protein expression. For example, microRNAs are known to play a regulatory role in glycosylation, a kind of posttranslational modification, in fact the most abundant posttranslational modification, which is essential to the structure and function of cell-surface proteins.
Now, in a new study conducted by researchers at New York University (NYU), miRNAs in the miR-200 family have been scrutinized. These miRNAs control the movement of cells in processes such as wound healing and tumor-cell metastasis. The NYU researchers hoped to determine if these miRNAs could reveal the role of three specific glycans that participate in the epithelial-to-mesenchymal transition, or the cell's switch from stationary to mobile behavior.
The results of this study appeared May 26 in the Proceedings of the National Academy of Sciences, in an article entitled, “miRNA proxy approach reveals hidden functions of glycosylation.” In particular, the study focused on a trio of glycans that are difficult to analyzed by traditional methods.
“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),” wrote the article’s authors. “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.”
The authors noted that miRNAs are far easier to analyze than glycosylation and are a useful tool to shed light on the role of glycosylation in human diseases and afflictions. This is especially important as carbohydrates play important roles in every disease, which we have yet to understand, noted Lara Mahal, an associate professor in NYU's Department of Chemistry and the study's senior author.
“Cleft palates, coronary artery disease, and other conditions involve biological pathways that we largely don't understand,” she explained. “MicroRNAs, our findings suggest, may offer a way to cut through the clutter to better see, and comprehend, how these afflictions are manifested.”
This point was amplified in the study’s conclusions, which indicated that miRNAs can act as a relatively simple proxies 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.
“Carbohydrates present a challenge for analysis because their complexity and 'noise' that accompanies their biosynthesis make it difficult to isolate how they are involved in cellular change,” explained Dr. Mahal. “Our results show that rather than trying to trace the intricacies of this molecule's activity, we can simply track miRNA.”