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Glycomics Meets Genomics, Epigenomics and Other High Throughput Omics for System Biology Studies

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Glycomics Meets Genomics, Epigenomics and Other High Throughput Omics for System Biology Studies COCHBI-1014; NO. OF PAGES 7 Available online at www.sciencedirect.com Glycomics meets genomics, epigenomics and other high throughput omics for system biology studies 1 1 2,3 Vlatka Zoldosˇ , Tomislav Horvat and Gordan Lauc Majority of eukaryotic proteins are glycosylated and their Both inherited (genetic) and acquired (environmental) glycan moieties have numerous important structural, functional factors that modulate glycosylation affect numerous mol- and regulatory roles. Because of structural complexity of ecular processes, including interactions with specific glycans and technological limitations glycomics, and receptors or half-life of numerous membrane proteins particularly glycoproteomics was not able to follow rapid [3]. Both quantitative and qualitative changes in the progress in genomics and proteomics over last 30 years. repertoire of glycan structures have been found in many However, the field of glycan has been progressing rapidly and complex diseases and cancer [4]. However, due to the first large-scale studies of the glycome have been completed structural complexity of glycans and technological limita- recently. These studies have revealed significant differences in tions the knowledge of functional importance of glycans glycome composition between individuals, which may is significantly lagging behind the knowledge of DNA and contribute to the human phenotypic variability. The current proteins. state-of-the-art in high-throughput glycomics and its integration with genomics, epigenomics and lipidomics is The development of high-throughput reviewed in this article. quantitative glycomic analysis Addresses Until only a few years ago glycan analysis was extremely 1 University of Zagreb, Faculty of Science, Zagreb, Croatia 2 laborious and complex, hampering large-scale studies of University of Zagreb, Faculty of Pharmacy and Biochemistry, Zagreb, Croatia the glycome. However, significant progress has been 3 Genos Ltd, Glycobiology Laboratory, Zagreb, Croatia made in the past few years and several methods for high-throughput glycan analysis now exist [5–9,10]. In Corresponding author: Lauc, Gordan ([email protected]) principle, three main analytical methods are being used for high-throughput analysis of glycans: liquid chroma- tography (high performance — HPLC and ultra perform- Current Opinion in Chemical Biology 2012, 17:xx–yy ance — UPLC, Figure 2), mass spectrometry (MS) and This review comes from a themed issue on Omics capillary electrophoresis (CE). An overview of some basic Edited by Pauline Rudd and Matthew Bogyo characteristics of these three methods is presented in Table 1, while more detailed description can be found in a recent review by Rakus and Mahal [11]. 1367-5931/$ – see front matter, # 2012 Elsevier Ltd. All rights In general, UPLC and CE enable reliable glycan quanti- reserved. fication. However, the development of analytical pro- http://dx.doi.org/10.1016/j.cbpa.2012.12.007 cedures for analysis of a particular biological system is demanding since glycan structures present in each chro- matographic/electrophoretic peak need to be individually Introduction determined by MS or egzoglycosidase digestion. In Nearly all membrane and secreted proteins as well as addition, separation of glycans is rarely complete, thus numerous intracellular proteins are modified by covalent each peak is a mixture of variable relative signal contri- addition of complex oligosaccharides (glycans), which butions originating from different glycans. MS analysis play roles in almost every biological process and are provides more structural details, but is generally less involved in every major disease [1,2]. A peculiarity quantitative. An additional problem lies in the fact that of glycan moieties of glycoproteins is that they are not signal response factors are different for different glycans, synthesized using a direct genetic template. Instead, they which complicates calculation of the derived traits, like result from the activity of several hundreds of enzymes galactosylation, fucosylation, sialylation, etc. organized in complex pathways. Changes in the activity and/or localization of any of the enzymes involved in It is estimated that many thousands of different glycans glycan biosynthesis will affect the final structure of a are attached to human proteins [11,12] and none of the glycan. Therefore, in addition to being defined by an currently available analytical methods can simultaneously individual’s genetic background, the glycome (defined as quantify all of them. Therefore, each analysis provides a set of all glycans in an analyzed tissue or organism) is only a limited insight into the complexity of the glycome. shaped by environmentally induced changes in gene On top of this, majority of glycoproteins have multiple expression (Figure 1). glycosylation sites, which can be occupied by different www.sciencedirect.com Current Opinion in Chemical Biology 2012, 17:1–7 Please cite this article in press as: Zoldosˇ V, et al.: Glycomics meets genomics, epigenomics and other high throughput omics for system biology studies, Curr Opin Chem Biol (2012), http:// dx.doi.org/10.1016/j.cbpa.2012.12.007 COCHBI-1014; NO. OF PAGES 7 2 Omics Figure 1 Genome SNP (genotype) Epigenome ON Change in chromatin Environment Gene expression structure OFF Proteome Glycome nucleosome with methylated histones unmethylated CpG site nucleosome with acetylated histones methylated CpG site Current Opinion in Chemical Biology Complex genetics and epigenetics of protein glycosylation. Glycans are synthetized by dynamic interaction between many enzymes and other proteins. In addition to sequence variation in DNA, glycosylation is strongly influenced by environmental effects. Environmental factors (like nutrition, stress, smoking, etc.) can act on the level of enzymatic reactions, but they can also modulate gene expression by epigenetic mechanisms like affecting DNA and histone modifications (such as histone acetylation and methylation). Cellular memory stored in epigenetic modifications can affect glycan synthesis long after the disappearance of the environmental factor itself. Rectangles represent individual genes; ovals in different colors represent different enzymes involved in biosynthetic pathway of glycan structures. glycan species with highly specialized functions. We are roles of the same glycans on different plasma proteins very far from understanding the role of glycans on actually blur protein-specific regulation of glycosylation majority of glycoproteins, but some prominent examples, of individual proteins. like IgG (which has been studied in more detail), clearly demonstrate the importance of glycans for structural High-throughput DNA analysis enabled one of stability and biological function of glycoproteins [3]. the largest bursts of discovery in human history Several large population studies of the plasma glycome Until middle of last decade two approaches were used to have been published until now [13–15]. They have all study the effects of genetic variation on complex human revealed a high variability in glycome composition be- diseases: genetic linkage studies and the candidate-gene tween individuals. However, besides age, which signifi- approach. Studies of genetic linkage used sets of scarce cantly affected galactosylation, all other environmental genetic markers and were consequently successful only in factors individually accounted only for a small fraction of identifying rare genetic mutations with high penetrance the observed variance, thus the main source of glycome and large-scale effects (monogenic, Mendelian disorders). variation between individuals is still not known. Inter- These studies were generally underpowered to detect estingly, when compared to the total plasma glycome, the effects of common genetic variants [16]. On the other glycome composition of a single isolated protein (IgG, hand, in majority of candidate gene studies, which were which is the only glycoprotein that has been analyzed at based on a priori hypotheses of biological plausibility, the population level) varied even more between individ- used sample sizes of only up to several hundred cases and uals [10]. This indicates that varying concentrations of controls and this led to results that were generally not plasma proteins and different structural and functional replicated in future studies [17,18]. Current Opinion in Chemical Biology 2012, 17:1–7 www.sciencedirect.com Please cite this article in press as: Zoldosˇ V, et al.: Glycomics meets genomics, epigenomics and other high throughput omics for system biology studies, Curr Opin Chem Biol (2012), http:// dx.doi.org/10.1016/j.cbpa.2012.12.007 COCHBI-1014; NO. OF PAGES 7 Glycomics meets genomics, epigenomics and other high throughput omics for system biology studies Zoldosˇ , Horvat and Lauc 3 Figure 2 GP 1 2 3 4 5 6 7 8a 8b 9 10 11 12 13 14 15 16a 16b 17 18a 18b 19 20 21 22 23 24 5 6 7 8 9 10 GU N-acetylglucosamine 6 4 2 α β β α Core Fucose α 6 6 Mannose β 4 β 4 β 4 Galactose α 3 N-acetylneuraminic acid α 6 β 4 β 2 Current Opinion in Chemical Biology Ultra performance liquid chromatography (UPLC) separation of the IgG glycome. Different chromatographic techniques can be used to separate glycome into individual glycans or groups of similar glycans. UPLC separation is frequently used to separate glycans attached to human IgG in a way that enables reliable quantification of nearly all individual components of the IgG glycome. However, UPLC analysis does not reveal structural details, thus individual chromatographic
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