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Epigenetic Regulation of Glycosylation
No full textExpression of glycosylation-related genes (or glycogenes) is strictly regulated by transcription factors and epigenetic processes, both in normal and in pathological conditions. In fact, glycosylation is an essential mechanism through which proteins and lipids are modified to perform a variety of biological events, to adapt to environment, and to interact with microorganisms. Many glycogenes with a role in normal development are epigenetically regulated. Essential studies were performed in the brain, where expression of glycogenes like MGAT5B, B4GALNT1, and ST8Sia1 are under the control of histone modifications, and in the immune system, where expression of FUT7 is regulated by both DNA methylation and histone modifications. At present, epigenetic regulation of glycosylation is still poorly described under physiological conditions, since the majority of the studies were focused on cancer. In fact, virtually all types of cancers display aberrant glycosylation, because of both genetic and epigenetic modifications on glycogenes. This is also true for many other diseases, such as inflammatory bowel disease, diabetes, systemic lupus erythematosus, IgA nephropathy, multiple sclerosis, and cardiovascular diseases. A deeper knowledge in epigenetic regulation of glycogenes is essential, since research in this field could be helpful in finding novel and personalized therapeutics
The link between gaucher disease and parkinson’s disease sheds light on old and novel disorders of sphingolipid metabolism
Full text linkSphingolipid metabolism starts with the biosynthesis of ceramide, a bioactive lipid and the backbone for the biosynthesis of complex sphingolipids such as sphingomyelin and glycosphingolipids. These are degraded back to ceramide and then to sphingosine, which enters the ceramide-sphingosine-1-phosphate signaling pathway or is further degraded. Several enzymes with multiple catalytic properties and subcellular localizations are thus involved in such metabolism. Hereditary defects of lysosomal hydrolases have been known for several years to be the cause of lysosomal storage diseases such as gangliosidoses, Gaucher disease, Niemann-Pick disease, Krabbe disease, Fabry disease, and Farber disease. More recently, many other inborn errors of sphingolipid metabolism have been recognized, involving enzymes responsible for the biosynthesis of ceramide, sphingomyelin, and glycosphingolipids. Concurrently, epidemiologic and biochemical evidence has established a link between Gaucher disease and Parkinson's disease, showing that glucocerebrosidase variants predispose individuals to α-synuclein accumulation and neurodegeneration even in the heterozygous status. This appears to be due not only to lysosomal overload of non-degraded glucosylceramide, but to the derangement of vesicle traffic and autophagy, including mitochondrial autophagy, triggered by both sphingolipid intermediates and misfolded proteins. In this review, old and novel disorders of sphingolipid metabolism, in particular those of ganglioside biosynthesis, are evaluated in light of recent investigations of the link between Gaucher disease and Parkinson's disease, with the aim of better understanding their pathogenic mechanisms and addressing new potential therapeutic strategies
Epigenetic regulation of glycosylation in cancer and other diseases
Full text linkIn the last few decades, the newly emerging field of epigenetic regulation of glycosylation acquired more importance because it is unraveling physiological and pathological mechanisms related to glycan functions. Glycosylation is a complex process in which proteins and lipids are modified by the attachment of monosaccharides. The main actors in this kind of modification are the glycoenzymes, which are translated from glycosylation‐related genes (or glycogenes). The expression of glycogenes is regulated by transcription factors and epigenetic mechanisms (mainly DNA methylation, histone acetylation and noncoding RNAs). This review focuses only on these last ones, in relation to cancer and other diseases, such as inflammatory bowel disease and IgA1 nephropathy. In fact, it is clear that a deeper knowledge in the fine‐tuning of glycogenes is essential for acquiring new insights in the glycan field, especially if this could be useful for finding novel and personalized therapeutics
Differential expression of beta1,3galactosyltransferase in human colon cells derived from adenocarcinomas or normal mucosa
No full textMouse C127 cells transfection with fucosyltransferase Fuc-TIII express masked Lewis X but not Lewis X antigen
No full textControl of sialyl Lewis X antigen expression in the colon by fucosyltransferase VI and beta4 GalNAcT-II
No full textSialyl Lewis X (sLex) is a well known carbohydrate antigen whose overexpression in cancer correlates with metastasis. In colon cancer, the molecular bases of sLex overexpression remain elusive. We have investigated sLex expression in normal and cancer colonic tissues and in cell lines as a function of the expression of fucosyltransferases and beta4GalNAcT-II. This enzyme, which is downregulated in colon cancers, is responsible for the biosynthesis of the Sda antigen [Siaalpha2,3(GalNAcbeta1,4)Galbeta1,4GlcNAc], whose biosynthesis competes with that of sLex. In colon cancers and cell lines, sLex expression correlates with a fucosyltransferase activity able to fucosylate 3'sialyllactosamine at low (0.5 mM) concentration. Transfection experiments with FucT-III, IV, V, VI and VII cDNAs in COS-7 cells indicate that only FucT-VI displays this property. In gastrointestinal cell lines, high levels of this fucosyltransferase activity are shown by cell lines expressing high levels of the FucT-VI transcript. In normal colon, sLex antigen is detectable upon de-acetylation but its expression does not correlate with any fucosyltransferase activity or transcript. Rather, we observed a significant correlation between sLex and the ratio between fucosyltransferase activity with 0.5 mM 3'sialyllactosamine and beta4GalNAcT-II activity. These data suggest that in both normal and cancer colonic tissues the biosynthesis of sLex is mainly due to FucT-VI or to a fucosyltransferase with similar kinetic properties, unknown at present.
In normal colon, but not in colon cancers, the fucosyltransferase activity above described is counteracted by competing glycosyltransferases, as the high beta4GalNAcT-II activity that synthesizes the alternative Sda antigen
beta 1,3-Galactosyltransferase beta 3Gal-T5 acts on the GlcNAcbeta 1-->3Galbeta 1-->4GlcNAcbeta 1-->R sugar chains of carcinoembryonic antigen and other N-linked glycoproteins and is down-regulated in colon adenocarcinomas.
No full textWe attempted to determine whether beta1,3-galactosyltransferase beta3Gal-T5 is involved in the biosynthesis of a specific subset of type 1 chain carbohydrates and expressed in a cancer-associated manner. We transfected Chinese hamster ovary (CHO) cells expressing Fuc-TIII with beta3Gal-T cDNAs and studied the relevant glycoconjugates formed. beta3Gal-T5 directs synthesis of Lewis type 1 antigens in CHO cells more efficiently than beta3Gal-T1, whereas beta3Gal-T2, -T3, and -T4 are almost unable to direct synthesis. In the clone expressing Fuc-TIII and beta3Gal-T5 (CHO-FT-T5), sialyl-Lewis a synthesis is strongly inhibited by swainsonine but not by benzyl-alpha-GalNAc, and sialyl-Lewis x is absent, although it is detected in the clones expressing Fuc-TIII and beta3Gal-T1 (CHO-FT-T1) or Fuc-TIII and beta3Gal-T2 (CHO-FT-T2). Endo-beta-galactosidase treatment of N- glycans prepared from clone CHO-FT-T5 releases (+/-NeuAcalpha2-->3)Galbeta1-->3[Fucalpha1-->4]GlcNAcbeta1-->3Gal but not GlcNAcbeta1-->3Gal or type 2 chain oligosaccharides, which are found in CHO-FT-T1 cells. This result indicates that beta3Gal-T5 expression prevents poly-N-acetyllactosamine and sialyl-Lewis x synthesis on N-glycans. Kinetic studies confirm that beta3Gal-T5 prefers acceptors having the GlcNAcbeta1-->3Gal end, including lactotriosylceramide. Competitive reverse transcriptase mediated-polymerase chain reaction shows that the beta3Gal-T5 transcript is expressed in normal colon mucosa but not or poorly in adenocarcinomas. Moreover, recombinant carcinoembryonic antigen purified from a CHO clone expressing Fuc-TIII and beta3Gal-T5 reacts with anti-sialyl-Lewis a and carries type 1 chains on oligosaccharides released by endo-beta-galactosidase. We conclude that beta3Gal-T5 down-regulation plays a relevant role in determining the cancer-associated glycosylation pattern of N-glycans
Molecular bases of sialyl Lewis x overexpression in colon cancer
No full textSialyl Lewis x (sLex) is a well known selectin ligand involved in metastasis. The molecular bases of its overexpression in colon cancer are still unclear. Here we show that FucT-VI is the main fucosyltransferase responsible for sLex biosynthesis in colonic tissues and a major regulator of sLex expression in colon cancer because: 1) in colon cancer specimens and cell lines sLex expression correlates with the activity of a fucosyltransferase able to fucosylate 3’ sialyllactosamine (3’SLN) at a low (0.5 mM) acceptor concentration. 2) In cells transiently transfected with FucT genes only FucT-VI displays this property. 3) In normal and cancer colon, FucT-VI transcript shows the highest level of expression (about 200 fg/pg actin, vs. 30 for FucT-III, 10 for FucT-IV, <1 for FucT-V while FucT-VII was undetectable). However, neither the FucT-VI transcript nor the activity on 3’SLN are increased in cancer tissues. In normal mucosa, sLex (which can be detected upon de-acetylation), does not correlate with FucT-VI activity. This is due to the concomitant high expression of beta4GalNAcT-II, the synthase of the Sda antigen [Sia alpha2,3(GalNAc beta1,4)Galbeta1,4GlcNAc], which competes with fucosyltransferases for 3’-sialylated type 2 chains and is downregulated in colon cancer. In fact, in normal mucosa sLex expression correlates with the ratio between the activities of FucT-VI and that of beta4GalNAcT-II. These findings explain why sLex antigen overexpression in cancer is not necessarily related to FucT-VI overexpression, and point to the balance between FucT-VI and beta4GalNAcT-II as a pivotal regulator of sLex in colon
Going Beyond Counting First Authors in Author Co-citation Analysis
Full text linkThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
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