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Epigenetic silencing of HNF1A associates with changes in the composition of the human plasma N- glycome

Protein glycosylation is an ubiquitous modification which affects structure and function of proteins. Our recent genome wide association study identified transcription factor HNF1A as an important regulator of plasma protein N- glycosylation. To evaluate the potential impact of epigenetic regulation of HNF1A on protein glycosylation we quantified its CpG methylation in 810 individuals. Correlations between methylation of four CpG sites and the composition of plasma and IgG glycomes were analyzed. Several statistically significant associations were observed between HNF1A methylation and plasma N- glycans, while there were no significant associations with IgG glycans. The most consistent association with HNF1A methylation was observed with the increase in the proportion of highly branched N-glycans. The hypothesis that inactivation of HNF1A promotes branching of glycans was supported by the analysis of plasma N- glycomes in 61 patients with inactivating mutations in HNF1A, where the increase in plasma glycan branching was observed as well. This study represents the first demonstration of epigenetic regulation of plasma N-glycome composition, suggesting potential mechanism by which epigenetic deregulation of the glycome may contribute to disease development.

DNA methylation; epigenetics; HNF1A; human plasma N-gylcome; pyrosequencing

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