Epigenetic silencing of<i>HNF1A</i>associates with changes in the composition of the human plasma<i>N</i>-glycome

Zoldoš, Vlatka; Horvat, Tomislav; Novokmet, Mislav; Cuenin, Cyrille; Mužinić, Ana; Pučić, Maja; Huffman, Jennifer E.; Gornik, Olga; Polašek, Ozren; Campbell, Harry; Hayward, Caroline; Wright, Alan F.; Rudan, Igor; Owen, Katharine R.; McCarthy, Mark I.; Herceg, Zdenko; Lauc, Gordan

doi:10.4161/epi.7.2.18918

Cited by 39 publications

(34 citation statements)

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“…Epigenetic silencing of HNF1A , a known master regulator of plasma protein fucosylation, has been shown to be associated with changes in the composition of the human plasma N-glycome [24]. In this study we find that methylation levels at other genes are also implicated in glycome composition, both in those with high heritabilities and those with a lower genetic contribution.…”

Section: Discussionmentioning

confidence: 52%

Glycosylation of Immunoglobulin G: Role of Genetic and Epigenetic Influences

et al. 2013

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ObjectiveTo determine the extent to which genetic and epigenetic factors contribute to variations in glycosylation of immunoglobulin G (IgG) in humans.Methods76 N-glycan traits in circulating IgG were analyzed by UPLC in 220 monozygotic and 310 dizygotic twin pairs from TwinsUK. A classical twin study design was used to derive the additive genetic, common and unique environmental components defining the variance in these traits. Epigenome-wide association analysis was performed using the Illumina 27k chip. Results51 of the 76 glycan traits studied have an additive genetic component (heritability, h 2)≥ 0.5. In contrast, 12 glycan traits had a low genetic contribution (h2<0.35). We then tested for association between methylation levels and glycan levels (P<2 x10-6). Among glycan traits with low heritability probe cg08392591 maps to a CpG island 5’ from the ANKRD11 gene, a p53 activator on chromosome 16. Probe cg26991199 maps to the SRSF10 gene involved in regulation of RNA splicing and particularly in regulation of splicing of mRNA precursors upon heat shock. Among those with high heritability we found cg13782134 (mapping to the NRN1L gene) and cg16029957 mapping near the QPCT gene to be array-wide significant. The proportion of array-wide epigenetic associations was significantly larger (P<0.005) among glycans with low heritability (42%) than in those with high heritability (6.2%).ConclusionsGlycome analyses might provide a useful integration of genetic and non-genetic factors to further our understanding of the role of glycosylation in both normal physiology and disease.

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Section: Discussionmentioning

confidence: 52%

Glycosylation of Immunoglobulin G: Role of Genetic and Epigenetic Influences

et al. 2013

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“…Second, glycosylation is not a simple addition to a protein, but an intricately and carefully regulated physiological process, which is affected by epigenetic regulation, which includes competing enzyme activities and the availability of activated monosaccharide donors 58 59 60 . Epigenetic regulation can modify biological structures and add/remove covalent groups, such as O- acetyl and methyl groups, which play important roles in the adaptation to specific environmental conditions 61 62 . Among these modifications, O- acetylation plays a crucial role in the regulation of ligand function of terminal sialic acids on N- glycans 63 .…”

Section: Discussionmentioning

confidence: 99%

Microfluidic Chip-LC/MS-based Glycomic Analysis Revealed Distinct N-glycan Profile of Rat Serum

Gao

Yau

Liu

et al. 2015

Sci Rep

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The rat is an important alternative for studying human pathology owing to certain similarities to humans. Glycomic studies on rat serum have revealed that variations in the N-glycans of glycoproteins correlated with disease progression, which is consistent with the findings in human serum. Therefore, we comprehensively characterized the rat serum N-glycome using microfluidic chip-LC-ESI-QTOF MS and MS/MS techniques. In total, 282 N-glycans, including isomers, were identified. This study is the first to present comprehensive profiling of N-glycans containing O-acetylated sialic acid, among which 27 N-glycans are novel. In addition, the co-existence of N-acetylneuraminic acid (NeuAc) and N-glycolylneuraminic acid (NeuGc) in a single N-glycan (‘mixed’ N-glycan) was detected and represents a new type of N-glycan in rat serum. The existence of O-acetylated sialic acid is the characteristic feature of rat serum that distinguishes it from mouse and human sera. Comparisons between the rat, mouse, and human serum glycomes revealed that the rat glycome is more similar to that of human sera than to that of mouse sera. Our findings highlight the similarities between the glycomic profile of rat and human sera and provided important selection criteria for choosing an appropriate animal model for pathological and pharmacological studies.

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“…In addition, we performed a gene expression analysis of relevant glycosyltransferases and evaluated the potential epigenetic influence on glycosyltransferase-encoding genes to better understand their complex association with cell surface glycosylation. The link between aberrant glycosylation and epigenetics in cancer is an emerging area of research that still remains poorly understood (28,29). Unlike irreversible genetic changes that affect the activity of these enzymes, epigenetic modifications can potentially be reversed by therapies such as de-methylation, which may be able to target defective glycosylation pathways to prevent metastasis in cancer (30).…”

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confidence: 99%

Specific Glycosylation of Membrane Proteins in Epithelial Ovarian Cancer Cell Lines: Glycan Structures Reflect Gene Expression and DNA Methylation Status

Anugraham

Jacob

Nixdorf

et al. 2014

Molecular & Cellular Proteomics

126

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Epithelial ovarian cancer is the fifth most common cause of cancer in women worldwide bearing the highest mortality rate among all gynecological cancers. Cell membrane glycans mediate various cellular processes such as cell signaling and become altered during carcinogenesis. The extent to which glycosylation changes are influenced by aberrant regulation of gene expression is nearly unknown for ovarian cancer and remains crucial in understanding the development and progression of this disease. To address this effect, we analyzed the membrane glycosylation of non-cancerous ovarian surface epithelial (HOSE 6.3 and HOSE 17.1) and serous ovarian cancer cell lines (SKOV 3, IGROV1, A2780, and OVCAR 3), the most common histotype among epithelial ovarian cancers. Nglycans were released from membrane glycoproteins by PNGase F and analyzed using nano-liquid chromatography on porous graphitized carbon and negative-ion electrospray ionization mass spectrometry (ESI-MS). Glycan structures were characterized based on their molecular masses and tandem MS fragmentation patterns. We identified characteristic glycan features that were unique to the ovarian cancer membrane proteins, namely the "bisecting N-acetyl-glucosamine" type N-glycans, increased levels of ␣ 2-6 sialylated N-glycans and "N,N-diacetyllactosamine" type N-glycans. These N-glycan changes were verified by examining gene transcript levels of the enzymes specific for their synthesis (MGAT3, ST6GAL1, and B4GALNT3) using qRT-PCR. We further evaluated the potential epigenetic influence on MGAT3 expression by treating the cell lines with 5-azacytidine, a DNA methylation inhibitor. For the first time, we provide evidence that MGAT3 expression may be epigenetically regulated by DNA hypomethylation, leading to the synthesis of the unique "bisecting GlcNAc" type N-glycans on the membrane proteins of ovarian cancer cells. Linking the observation of specific N-glycan substructures and their complex association with epigenetic programming of their associated synthetic enzymes in ovarian cancer could potentially be used for the development of novel anti-glycan drug targets and clinical diagnostic tools. Molecular & Cellular

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Epigenetic silencing ofHNF1Aassociates with changes in the composition of the human plasmaN-glycome

Abstract: (2012) Epigenetic silencing of HNF1A associates with changes in the composition of the human plasma N-glycome, Epigenetics, 7:2, 164-172,

Cited by 39 publications

References 41 publications

Glycosylation of Immunoglobulin G: Role of Genetic and Epigenetic Influences

Glycosylation of Immunoglobulin G: Role of Genetic and Epigenetic Influences

Microfluidic Chip-LC/MS-based Glycomic Analysis Revealed Distinct N-glycan Profile of Rat Serum

Specific Glycosylation of Membrane Proteins in Epithelial Ovarian Cancer Cell Lines: Glycan Structures Reflect Gene Expression and DNA Methylation Status

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