You will be presented with the abstract, introduction, and discussion section from a biomedical research article. Your task is to create a summary that a layperson can understand, capturing the essence of the research article. Keep essential scientific terms, but ensure that the language remains clear and the concepts are explained in an uncomplicated manner.

Title: Genomics Meets Glycomics—The First GWAS Study of Human N-Glycome Identifies HNF1α as a Master Regulator of Plasma Protein Fucosylation}
Article:
Abstract:
Over half of all proteins are glycosylated, and alterations in glycosylation have been observed in numerous physiological and pathological processes. Attached glycans significantly affect protein function; but, contrary to polypeptides, they are not directly encoded by genes, and the complex processes that regulate their assembly are poorly understood. A novel approach combining genome-wide association and high-throughput glycomics analysis of 2, 705 individuals in three population cohorts showed that common variants in the Hepatocyte Nuclear Factor 1α( HNF1α) and fucosyltransferase genes FUT6 and FUT8 influence N-glycan levels in human plasma. We show that HNF1α and its downstream target HNF4α regulate the expression of key fucosyltransferase and fucose biosynthesis genes. Moreover, we show that HNF1α is both necessary and sufficient to drive the expression of these genes in hepatic cells. These results reveal a new role for HNF1α as a master transcriptional regulator of multiple stages in the fucosylation process. This mechanism has implications for the regulation of immunity, embryonic development, and protein folding, as well as for our understanding of the molecular mechanisms underlying cancer, coronary heart disease, and metabolic and inflammatory disorders.
Introduction:
Glycosylation is a post-translational modification that enriches protein complexity and function. Over half of all known proteins are modified by covalently bound glycans, which are important for normal physiological processes, including protein folding, degradation and secretion, cell signalling, immune function and transcription[1]–[4]. Configuration and composition of attached glycans significantly change the structure and activity of polypeptide portions of glycoproteins[5] and since this process is not template driven, complexity of the glycoproteome is estimated to be several orders of magnitude greater than for the proteome itself[6]. Disregulation of glycosylation is associated with a wide range of diseases, including cancer, diabetes, cardiovascular, congenital, immunological and infectious disorders[1],[3],[7]. Enzymes that are involved in glycosylation may therefore be promising targets for therapy[8]. The most prominent example of the importance of N-glycosylation is the group of rare diseases named congenital disorders of glycosylation[9] where different mutations in the biosynthesis pathway of N-glycans cause significant mortality and extensive motor, immunological, digestive and neurological symptoms[10],[11]. Due to experimental limitations in quantifying glycans in complex biological samples, our understanding of the genetic regulation of glycosylation is currently very limited[12]. However, recent technological advances have allowed reliable, high-throughput quantification of N-glycans[13], which now permits investigation of the genetic regulation and biological roles of glycan structures and brings glycomics into line with genomics, proteomics and metabolomics[14]. Recently we completed the first comprehensive population study of human plasma N-glycome which revealed variability that by far exceeds the variability of proteins and DNA[15]. However, within a single individual composition of plasma glycome is rather stable[16] and environmental factors have limited impact on the majority of glycans[17]. Specific altered glyco-phenotypes that can be associated with specific pathologies were also identified to exist in a population[18]. Variations in glycosylation are of great physiological significance as alterations in glycans significantly change the structure and function of polypeptide parts of glycoproteins[5]. A particularly interesting element of protein glycosylation is the addition of fucose to non-reducing ends of N-glycans. Fucose is a relatively novel sugar in evolutionary terms with two important structural features that distinguishes it from all other mammalian six-carbon monosaccharides; it lacks a hydroxyl group on the carbon at the 6-position and is the only monosaccharide that is in the L-configuration. The conversion of GDP-mannose to GDP-fucose is catalyzed by two enzymes( GMD and FX) that display remarkable evolutionary conservation[19],[20]. On the other hand, the large family of genes that add fucose to proteins and lipids( fucosyltranferases, FUTs) has a very complex evolutionary history, including several more recent events specific to primates[21]. In mammals, fucose-containing glycans have important roles in blood transfusion reactions, in the selectin-mediated leukocyte-endothelial adhesion that initiates an inflammatory response, in host-microbe interactions, and numerous ontogenic events[10],[19]. Acute phase proteins have altered fucosylation in many diseases[22] and changes in the levels of fucosylated glycans have been shown to be associated with several important pathological processes, including cancer[23]. Hepatocyte nuclear factor 1α( HNF1α) and its downstream target HNF4α are transcription factors that regulate gene expression in both the liver and pancreas in a tissue-specific manner and are key regulators of metabolic genes[24]. Mutations in the encoding genes HNF1α and HNF4α cause Maturity Onset Diabetes of the Young( MODY) types 3 and 1 respectively[25],[26]. Recently, HNF1α single nucleotide polymorphisms( SNPs) have been associated with plasma C-reactive protein( CRP)[27], LDL cholesterol and gamma glutamyltransferase( GGT)[28], and coronary heart disease[29]. HNF4α variants have been associated with ulcerative colitis[30] and with the plasma concentrations of CRP and apolipoprotein A1( APOA1)[31]. Currently there is little evidence to link these transcription factors with fucose metabolism and the upstream mechanisms regulating fucosylation pathways are unknown.
Discussion:
By performing the first genome-wide association analysis( GWAS) of protein glycosylation we have taken the first steps towards the mapping of the complex network of genes that regulate protein N-glycosylation. We also identified common variants in three genes which exert a relatively strong influence on N-glycans in plasma( 1–6% of variance explained). Importantly, all of the identified genes( FUT6, FUT8 and HNF1α) are involved in fucosylation, indicating that the addition of this unusual sugar may be a rate-limiting step in N-glycan synthesis. A gene encoding the transcription factor HNF1α, with previously unknown biological links to glycosylation, is shown to be strongly associated with the relative proportions of plasma N-glycans. The possible function( s) of HNF1α are a focus of intense current interest following its recently reported associations in GWAS with plasma C-reactive protein( CRP)[27], gamma-glutamyl transferase( GGT)[28], LDL cholesterol and apolipoprotein[29],[31] and coronary artery disease[29],[46]. Our analysis of gene knockdowns( RNAi) showed that HNF1α is an upstream regulator of several key genes involved in different stages of the fucosylation pathway. We have demonstrated that HNF1α binds the promoters in vivo, and is necessary and sufficient for the in vitro expression, of two genes, fucokinase and GMDS, required for de novo and salvage pathways of fucose synthesis, respectively( Figure 5C). Fucose synthesis is the rate limiting step for fucosylation in eukaryotes and prokaryotes[35] and, by up-regulating its synthesis, HNF1α increases the availability of fucose to the glycosylation machinery. In addition, HNF1α directly regulates the expression of several fucosyltransferase( FUT) genes( Figure 5D). Our results also demonstrate that HNF1α reciprocally regulates core versus antennary fucosylation; while activating FUTs involved in antennary fucosylation, HNF1α represses FUT8, which adds fucose to the core-GlcNAc. In this way, HNF1α decreases the consumption of GDP-fucose for core-fucosylation, and further increases the pool of fucose available for antennary fucosylation. Having shown this novel regulation of fucosylation genes, we scanned earlier genome wide studies for HNF factors to identify whether these genes were picked up. In fact, other genome wide studies support our findings. Boyd et al( 2009) mapped HNF4α binding to both FUT2 and FUT5 in intestinal epithelial cells[42]. A genome wide prediction study for HNF4α functional binding sites identified FUT6, FUT5, FUT9, GMDS and FUT12 as functional targets[47]. We hypothesize that the role of HNF1α and its transcriptional co-factor HNF4α in the regulation of fucosylation is an essential part of mounting an acute phase response to infection in humans. Antennary fucosylation of their glycoprotein ligands is needed for binding of E-, L- and P-selectins to their target cells and the initiation of inflammation[48]. The decrease in fucosylation in the rare Leukocyte Adhesion Deficiency II( LAD II) impairs neutrophil function, which can be restored by oral administration of fucose[49]. Recently, we have reported moderate correlations between fucosylated plasma N-glycans and components of the acute phase response[15], which are also highly glycosylated and have high content of antennary-fucose[50]. Mounting a successful acute-phase response requires a rapid increase in the concentration of acute-phase proteins and this in turn is dependent on their efficient fucosylation. Our results indicate that fucosylation is a rate-limiting step in plasma protein glycosylation, and by both increasing de novo and salvage synthesis of GDP-fucose, up-regulation of antennary fucosyltransferases and down-regulation of core-fucosyltransferase, HNF1α appears to be a master regulator of this process. Variants in HNF1α and HNF4α genes were previously reported to be associated with concentrations of acute phase proteins in human plasma[24],[27]. Plasma protein fucosylation plays an important role in inflammation[22] and the central role of HNF1α in the regulation of multiple genes involved in fucosylation may be the molecular mechanism behind the reported association between common variants in HNF1α and inflammatory markers( such as CRP) as well as several diseases in which inflammation plays a key pathogenic role( such as coronary artery disease, inflammatory bowel disease and cancer).
By combining recently developed high-throughput glycan analysis with genome-wide association study , we performed the first comprehensive analysis of common genetic polymorphisms that affect protein glycosylation . Over half of all proteins are glycosylated; but , due to difficulties in glycan analysis and the absence of a genetic template for their synthesis , knowledge about the complex processes that regulate glycan assembly is still limited . We demonstrated that HNF1α regulates the expression of key fucosyltransferase and fucose biosynthesis genes and acts as a master regulator of plasma protein fucosylation . Proper protein fucosylation is essential in numerous processes including inflammation , cancer , and coronary heart disease , thus the identification of a master regulator of plasma protein fucosylation has important implications for understanding both normal biological functions and disease processes .