title: Epigenetic silencing of HNF1A associates with changes in the composition of the human plasma N-glycome.
abstract: Protein glycosylation is a ubiquitous modification that affects the structure and function of proteins. Our recent genome wide association study identified transcription factor HNF1A as an important regulator of plasma protein glycosylation. To evaluate the potential impact of epigenetic regulation of HNF1A on protein glycosylation we analyzed CpG methylation in 810 individuals. The association between methylation of four CpG sites and the composition of plasma and IgG glycomes was analyzed. Several statistically significant associations were observed between HNF1A methylation and plasma 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 glycans in the plasma N-glycome. 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 also observed. This study represents the first demonstration of epigenetic regulation of plasma glycome composition, suggesting a potential mechanism by which epigenetic deregulation of the glycome may contribute to disease development.
authors.affiliation: University of Zagreb Faculty of Science, University of Zagreb, Zagreb, Croatia.
authors.forename: Vlatka
authors.initials: V
authors.lastname: Zoldoš
authors.forename: Tomislav
authors.initials: T
authors.lastname: Horvat
authors.forename: Mislav
authors.initials: M
authors.lastname: Novokmet
authors.forename: Cyrille
authors.initials: C
authors.lastname: Cuenin
authors.forename: Ana
authors.initials: A
authors.lastname: Mužinić
authors.forename: Maja
authors.initials: M
authors.lastname: Pučić
authors.forename: Jennifer E
authors.initials: JE
authors.lastname: Huffman
authors.forename: Olga
authors.initials: O
authors.lastname: Gornik
authors.forename: Ozren
authors.initials: O
authors.lastname: Polašek
authors.forename: Harry
authors.initials: H
authors.lastname: Campbell
authors.forename: Caroline
authors.initials: C
authors.lastname: Hayward
authors.forename: Alan F
authors.initials: AF
authors.lastname: Wright
authors.forename: Igor
authors.initials: I
authors.lastname: Rudan
authors.forename: Katharine
authors.initials: K
authors.lastname: Owen
authors.forename: Mark I
authors.initials: MI
authors.lastname: McCarthy
authors.forename: Zdenko
authors.initials: Z
authors.lastname: Herceg
authors.forename: Gordan
authors.initials: G
authors.lastname: Lauc
mesh_terms: D002460:Cell Line; D002851:Chromatography, High Pressure Liquid; D018899:CpG Islands / Q000235:genetics; D019175:DNA Methylation / Q000235:genetics; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000235:genetics; D020868:Gene Silencing; D056726:Genetic Association Studies; D054794:Glycomics; D051538:Hepatocyte Nuclear Factor 1-alpha / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D020084:Long Interspersed Nucleotide Elements / Q000235:genetics; D011134:Polysaccharides / Q000097:blood* / Q000737:chemistry
chemical_list: C496487:HNF1A protein, human; D051538:Hepatocyte Nuclear Factor 1-alpha; D011134:Polysaccharides