Mapping of the gene network that regulates glycan clock of ageing
Azra Frkatović-Hodžić (Genos Glycoscience Research Laboratory)
Anika Mijakovac (University of Zagreb)
Karlo Miškec (University of Zagreb)
Arina Nostaeva (Novosibirsk State University)
Sodbo Z. Sharapov (Chemistry Faculty of M. V. Lomonosov Moscow State University)
Arianna Landini (The University of Edinburgh)
Toomas Haller (University of Tartu)
Erik Ben van den Akker (Leiden University Medical Center, TU Delft - Pattern Recognition and Bioinformatics)
Sapna Sharma (German Center for Diabetes Research (DZD), Helmholtz Zentrum München)
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Abstract
Glycans are an essential structural component of immunoglobulin G (IgG) that modulate its structure and function. However, regulatory mechanisms behind this complex posttranslational modification are not well known. Previous genome-wide association studies (GWAS) identified 29 genomic regions involved in regulation of IgG glycosylation, but only a few were functionally validated. One of the key functional features of IgG glycosylation is the addition of galactose (galactosylation), a trait which was shown to be associated with ageing. We performed GWAS of IgG galactosylation (N=13,705) and identified 16 significantly associated loci, indicating that IgG galactosylation is regulated by a complex network of genes that extends beyond the galactosyltransferase enzyme that adds galactose to IgG glycans. Gene prioritization identified 37 candidate genes. Using a recently developed CRISPR/dCas9 system we manipulated gene expression of candidate genes in the in vitro IgG expression system. Upregulation of three genes, EEF1A1, MANBA and TNFRSF13B, changed the IgG glycome composition, which confirmed that these three genes are involved in IgG galactosylation in this in vitro expression system.
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