Insights into miRNA regulation of the human glycome

Abstract

Glycosylation is an intricate process requiring the coordinated action of multiple proteins, including glycosyltransferases, glycosidases, sugar nucleotide transporters and trafficking proteins. Work by several groups points to a role for microRNA (miRNA) in controlling the levels of specific glycosyltransferases involved in cancer, neural migration and osteoblast formation. Recent work in our laboratory suggests that miRNA are a principal regulator of the glycome, translating genomic information into the glycocode through tuning of enzyme levels. Herein we overlay predicted miRNA regulation of glycosylation related genes (glycogenes) onto maps of the common N-linked and O-linked glycan biosynthetic pathways to identify key regulatory nodes of the glycome. Our analysis provides insights into glycan regulation and suggests that at the regulatory level, glycogenes are non-redundant.

Keywords: Carbohydrate pathways; Glycan biosynthesis; Glycan regulation; Glycogenes; Glycosylation; MicroRNA; miRNA.

Figure 1. MiRNA regulatory map for glycogenes in the N-linked glycosylation pathway

A schematic illustration of the N-linked glycan pathway with the relevant glycosylation enzymes is shown. Synthetic pathways for Glc₂Man₉GlcNAc₂-dolichol precursor, high-mannose, hybrid and complex oligosaccharides are indicated. The multicomponent oligosaccharyltransferase (OST) is represented by STT3A and STT3B (purple), the genes that encode for the catalytic subunits. The size of the circles (nodes) represents the total number of miRNA binding sites (both conserved and non-conserved) predicted within the 3′UTR of the indicated glycogenes (see Methods for details, scale shown in inset). Color of circle corresponds to the enzyme class (see inset legend). Where multiple isoforms of the same glycogene exist, the isoform is indicated within the circle). Linkages between the nodes illustrate the various paths of the biosynthetic pathway and the resulting glycan structures are shown in the grey boxes. “Highly regulated” glycogenes are denoted with an asterisk (*).

Figure 2. MiRNA regulatory map for glycogenes in the O-linked glycosylation pathway

A schematic illustration of the O-linked glycan pathway with the relevant glycosylation enzymes is shown. Pathway is annotated as in Figure 1. “Highly regulated” glycogenes are denoted with an asterisk (*).

Figure 3. MiRNA regulatory map for glycogenes involved in polyLacNAc and sialoside biosynthesis

A schematic illustration of the glycogenes involved in the terminal modification processing steps leading to (A) polyLacNAc structures and (B) sialosides. Pathway is annotated as in Figure 1. “Highly regulated” glycogenes are denoted with an asterisk (*).

Figure 4. MiRNA regulatory map for glycogenes involved in blood group and Lewis antigens

A schematic illustration of the glycogenes involved in the terminal modification processing steps leading to blood group and Lewis antigen structures on (A) Type I and (B) Type II LacNAc cores. Pathway is annotated as in Figure 1. “Highly regulated” glycogenes are denoted with an asterisk (*).