Mapping the Gene Network That Regulates the Glycan Clock of Ageing

01-03-2024

“[...] we were able to confirm the functional role of three genes (MANBA, TNFRSF13B and EEF1A1) in the IgG galactosylation pathway [...]” 

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BUFFALO, NY- January 3, 2024 – A new research paper was published in Aging (listed by MEDLINE/PubMed as "Aging (Albany NY)" and "Aging-US" by Web of Science) Volume 15, Issue 24, entitled, “Mapping of the gene network that regulates glycan clock of ageing.”

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.

In this new study, researchers Azra Frkatović-Hodžić, Anika Mijakovac, Karlo Miškec, Arina Nostaeva, Sodbo Z. Sharapov, Arianna Landini, Toomas Haller, Erik van den Akker, Sapna Sharma, Rafael R. C. Cuadrat, Massimo Mangino, Yong Li, Toma Keser, Najda Rudman, Tamara Štambuk, Maja Pučić-Baković, Irena Trbojević-Akmačić, Ivan Gudelj, Jerko Štambuk, Tea Pribić, Barbara Radovani, Petra Tominac, Krista Fischer, Marian Beekman, Manfred Wuhrer, Christian Gieger, Matthias B. Schulze, Clemens Wittenbecher, Ozren Polasek, Caroline Hayward, James F. Wilson, Tim D. Spector, Anna Köttgen, Frano Vučković, Yurii S. Aulchenko, Aleksandar Vojta, Jasminka Krištić, Lucija Klarić, Vlatka Zoldoš, and Gordan Lauc from Genos Glycoscience Research Laboratory, University of Zagreb, Novosibirsk State University, Lomonosov Moscow State University, University of Edinburgh, University of Tartu, Leiden University Medical Center, Delft University of Technology, Helmholtz Zentrum Muenchen, German Center for Diabetes Research (DZD), King’s College London, Guy’s and St Thomas’ Foundation Trust, University of Freiburg, University of Rijeka, German Institute of Human Nutrition Potsdam-Rehbruecke, University of Potsdam, Harvard T.H. Chan School of Public Health, Chalmers University of Technology, University of Split School of Medicine, Algebra University College, Johns Hopkins Bloomberg School of Public Health, and Institute of Cytology and Genetics SB RAS 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.

“Here, we conducted a GWAS of IgG galactosylation phenotypes in a study that almost doubles the sample size (N=13,705) compared to previous GWAS of IgG N-glycome [33] and focused on the genes with in silico evidence for involvement in the IgG galactosylation process.”

Gene prioritization identified 37 candidate genes. Using a recently developed CRISPR/dCas9 system, the researchers 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.

“Further research is needed to fully elucidate [the] functional mechanism behind their role in ageing and to reveal the complete network of gene interactions regulating the complex process of IgG glycosylation.”

Read the full paper: DOI: https://doi.org/10.18632/aging.205106 

Corresponding Authors: Azra Frkatović-Hodžić, Gordan Lauc

Corresponding Emails: afrkatovic@genos.hr, glauc@genos.hr

Keywords: genome-wide association study, glycosylation, glycan clock, immunoglobulin G, CRISPR/dCas9

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About Aging-US:

Launched in 2009, Aging (Aging-US) publishes papers of general interest and biological significance in all fields of aging research and age-related diseases, including cancer—and now, with a special focus on COVID-19 vulnerability as an age-dependent syndrome. Topics in Aging go beyond traditional gerontology, including, but not limited to, cellular and molecular biology, human age-related diseases, pathology in model organisms, signal transduction pathways (e.g., p53, sirtuins, and PI-3K/AKT/mTOR, among others), and approaches to modulating these signaling pathways.

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