Genos Glycoscience Research Laboratory, Zagreb, Croatia.
Department of Biology, Division of Molecular Biology, Faculty of Science, University of Zagreb, Zagreb, Croatia.
Aging (Albany NY). 2023 Dec 26;15(24):14509-14552. doi: 10.18632/aging.205106.
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 IgG expression system. Upregulation of three genes, and , changed the IgG glycome composition, which confirmed that these three genes are involved in IgG galactosylation in this expression system.
糖基是免疫球蛋白 G（IgG）的重要结构组成部分，调节其结构和功能。然而，这种复杂的翻译后修饰的调节机制还不是很清楚。先前的全基因组关联研究（GWAS）确定了 29 个与 IgG 糖基化调节相关的基因组区域，但只有少数几个得到了功能验证。IgG 糖基化的一个关键功能特征是添加半乳糖（半乳糖基化），这一特征与衰老有关。我们对 IgG 半乳糖基化（N=13705）进行了 GWAS 研究，鉴定出 16 个与 IgG 半乳糖基化显著相关的位点，表明 IgG 半乳糖基化受一个复杂的基因网络调控，这个网络超越了向 IgG 聚糖添加半乳糖的半乳糖基转移酶。基因优先级确定了 37 个候选基因。使用最近开发的 CRISPR/dCas9 系统，我们在 IgG 表达系统中操纵候选基因的表达。三个基因（和）的上调改变了 IgG 聚糖组成，这证实了这三个基因在这个 IgG 表达系统中参与 IgG 半乳糖基化。
