Genomics Meets Glycomics—The First GWAS Study of Human N-Glycome Identifies HNF1α as a Master Regulator of Plasma Protein Fucosylation
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{"title"=>"Genomics meets glycomics-the first gwas study of human N-glycome identifies HNF1A as a master regulator of plasma protein fucosylation", "type"=>"journal", "authors"=>[{"first_name"=>"Gordan", "last_name"=>"Lauc", "scopus_author_id"=>"7003975504"}, {"first_name"=>"Abdelkader", "last_name"=>"Essafi", "scopus_author_id"=>"10340564900"}, {"first_name"=>"Jennifer E.", "last_name"=>"Huffman", "scopus_author_id"=>"26654219700"}, {"first_name"=>"Caroline", "last_name"=>"Hayward", "scopus_author_id"=>"35369845200"}, {"first_name"=>"Ana", "last_name"=>"Knežević", "scopus_author_id"=>"26321702800"}, {"first_name"=>"Jayesh J.", "last_name"=>"Kattla", "scopus_author_id"=>"16645922300"}, {"first_name"=>"Ozren", "last_name"=>"Polašek", "scopus_author_id"=>"8232027400"}, {"first_name"=>"Olga", "last_name"=>"Gornik", "scopus_author_id"=>"16401725200"}, {"first_name"=>"Veronique", "last_name"=>"Vitart", "scopus_author_id"=>"56920729200"}, {"first_name"=>"Jodie L.", "last_name"=>"Abrahams", "scopus_author_id"=>"23988322500"}, {"first_name"=>"Maja", "last_name"=>"Pučić", "scopus_author_id"=>"35754931400"}, {"first_name"=>"Mislav", "last_name"=>"Novokmet", "scopus_author_id"=>"23568362300"}, {"first_name"=>"Irma", "last_name"=>"Redžić", "scopus_author_id"=>"35194533600"}, {"first_name"=>"Susan", "last_name"=>"Campbell", "scopus_author_id"=>"7403000233"}, {"first_name"=>"Sarah H.", "last_name"=>"Wild", "scopus_author_id"=>"7103086309"}, {"first_name"=>"Fran", "last_name"=>"Borovečki", "scopus_author_id"=>"6506641236"}, {"first_name"=>"Wei", "last_name"=>"Wang", "scopus_author_id"=>"37032157400"}, {"first_name"=>"Ivana", "last_name"=>"Kolčić", "scopus_author_id"=>"8421508800"}, {"first_name"=>"Lina", "last_name"=>"Zgaga", "scopus_author_id"=>"57192975891"}, {"first_name"=>"Ulf", "last_name"=>"Gyllensten", "scopus_author_id"=>"7004953409"}, {"first_name"=>"James F.", "last_name"=>"Wilson", "scopus_author_id"=>"56920724500"}, {"first_name"=>"Alan F.", "last_name"=>"Wright", "scopus_author_id"=>"35402433000"}, {"first_name"=>"Nicholas D.", "last_name"=>"Hastie", "scopus_author_id"=>"7007175006"}, {"first_name"=>"Harry", "last_name"=>"Campbell", "scopus_author_id"=>"56998183500"}, {"first_name"=>"Pauline M.", "last_name"=>"Rudd", "scopus_author_id"=>"7102279599"}, {"first_name"=>"Igor", "last_name"=>"Rudan", "scopus_author_id"=>"7007138278"}], "year"=>2010, "source"=>"PLoS Genetics", "identifiers"=>{"sgr"=>"84975742481", "doi"=>"10.1371/journal.pgen.1001256", "pui"=>"361011539", "pmid"=>"21203500", "scopus"=>"2-s2.0-84975742481", "issn"=>"15537404", "isbn"=>"1553-7404 (Electronic)\\r1553-7390 (Linking)"}, "id"=>"a873389b-f689-318b-a5dc-7b9f2b7754d3", "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.", "link"=>"http://www.mendeley.com/research/genomics-meets-glycomicsthe-first-gwas-study-human-nglycome-identifies-hnf1a-master-regulator-plasma", "reader_count"=>119, "reader_count_by_academic_status"=>{"Unspecified"=>2, "Professor > Associate Professor"=>7, "Librarian"=>6, "Researcher"=>33, "Student > Doctoral Student"=>5, "Student > Ph. D. Student"=>34, "Student > Postgraduate"=>4, "Student > Master"=>9, "Other"=>7, "Student > Bachelor"=>3, "Lecturer"=>1, "Professor"=>8}, "reader_count_by_user_role"=>{"Unspecified"=>2, "Professor > Associate Professor"=>7, "Librarian"=>6, "Researcher"=>33, "Student > Doctoral Student"=>5, "Student > Ph. D. Student"=>34, "Student > Postgraduate"=>4, "Student > Master"=>9, "Other"=>7, "Student > Bachelor"=>3, "Lecturer"=>1, "Professor"=>8}, "reader_count_by_subject_area"=>{"Unspecified"=>3, "Biochemistry, Genetics and Molecular Biology"=>16, "Mathematics"=>2, "Agricultural and Biological Sciences"=>71, "Medicine and Dentistry"=>18, "Arts and Humanities"=>1, "Pharmacology, Toxicology and Pharmaceutical Science"=>2, "Chemistry"=>3, "Computer Science"=>1, "Immunology and Microbiology"=>2}, "reader_count_by_subdiscipline"=>{"Medicine and Dentistry"=>{"Medicine and Dentistry"=>18}, "Chemistry"=>{"Chemistry"=>3}, "Immunology and Microbiology"=>{"Immunology and Microbiology"=>2}, "Agricultural and Biological Sciences"=>{"Agricultural and Biological Sciences"=>71}, "Computer Science"=>{"Computer Science"=>1}, "Biochemistry, Genetics and Molecular Biology"=>{"Biochemistry, Genetics and Molecular Biology"=>16}, "Mathematics"=>{"Mathematics"=>2}, "Unspecified"=>{"Unspecified"=>3}, "Pharmacology, Toxicology and Pharmaceutical Science"=>{"Pharmacology, Toxicology and Pharmaceutical Science"=>2}, "Arts and Humanities"=>{"Arts and Humanities"=>1}}, "reader_count_by_country"=>{"Sweden"=>1, "United States"=>1, "Ireland"=>1, "Mexico"=>1, "United Kingdom"=>2, "Lithuania"=>1, "France"=>1, "Spain"=>2, "Croatia"=>2}, "group_count"=>8}

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Figshare

  • {"files"=>["https://ndownloader.figshare.com/files/809645"], "description"=>"<p>Quantile-quantile plots for test statistics (a–c) and forest plots of the most significant SNPs (d–f) from the meta-analysis of DG1, DG7, and DG9. −Log<sub>10</sub> of the association p-values are plotted against −log<sub>10</sub> of the expected p-value under the null hypothesis of no association for the meta-analysis. The effect size estimates for each individual population and the meta-analysis are shown along with their standard errors. The effect size presented is the β-coefficient, which represents a change in glycan levels measured in standard deviation units (adjusted for covariates) per copy of the allele modelled. The mean effect size estimates are represented by a square for individual cohorts where the size is proportional to its contribution to the pooled effect size.</p>", "links"=>[], "tags"=>["plots"], "article_id"=>479971, "categories"=>["Biochemistry", "Genetics"], "users"=>["Gordan Lauc", "Abdelkader Essafi", "Jennifer E. Huffman", "Caroline Hayward", "Ana Knežević", "Jayesh J. Kattla", "Ozren Polašek", "Olga Gornik", "Veronique Vitart", "Jodie L. Abrahams", "Maja Pučić", "Mislav Novokmet", "Irma Redžić", "Susan Campbell", "Sarah H. Wild", "Fran Borovecki", "Wei Wang", "Ivana Kolčić", "Lina Zgaga", "Ulf Gyllensten", "James F. Wilson", "Alan F. Wright", "Nicholas D. Hastie", "Harry Campbell", "Pauline M. Rudd", "Igor Rudan"], "doi"=>"https://dx.doi.org/10.1371/journal.pgen.1001256.g002", "stats"=>{"downloads"=>0, "page_views"=>4, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Quantile_8211_quantile_plots_and_forest_plots_/479971", "title"=>"Quantile–quantile plots and forest plots.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2010-12-23 02:46:11"}
  • {"files"=>["https://ndownloader.figshare.com/files/810065"], "description"=>"<p>A). Diagram showing HNF1α and HNF4α regulation of pathways involved in fucose synthesis. B). Pathways of core (tri-mannosyl-chitobiose) and antennary fucosylation and their proposed regulation by the transcription factors Hnf1α and Hnf4α, encoded by the <i>HNF1α</i> and <i>HNF4α</i> genes respectively. Red arrows indicate genes that are targets of Hnf1α/Hnf4α. Solid lines show direct regulation and dashed lines show indirect regulation of the FUT genes shown. Genes shown in blue depict GWAS identified genes (<i>HNF1α</i>, <i>FUT6</i> and <i>FUT8</i>). Abbreviations: Neu5Ac, N-Acetylneuraminic (sialic) acid; GlcNAc, N-acetylglucosamine; Man, mannose; Gal, galactose; poly-LacNAc, Galβ1,4GlcNAc (LacNAc) antennary chains; Asn, asparagine residue on glycosylated protein.</p>", "links"=>[], "tags"=>["fucosylation"], "article_id"=>480403, "categories"=>["Biochemistry", "Genetics"], "users"=>["Gordan Lauc", "Abdelkader Essafi", "Jennifer E. Huffman", "Caroline Hayward", "Ana Knežević", "Jayesh J. Kattla", "Ozren Polašek", "Olga Gornik", "Veronique Vitart", "Jodie L. Abrahams", "Maja Pučić", "Mislav Novokmet", "Irma Redžić", "Susan Campbell", "Sarah H. Wild", "Fran Borovecki", "Wei Wang", "Ivana Kolčić", "Lina Zgaga", "Ulf Gyllensten", "James F. Wilson", "Alan F. Wright", "Nicholas D. Hastie", "Harry Campbell", "Pauline M. Rudd", "Igor Rudan"], "doi"=>"https://dx.doi.org/10.1371/journal.pgen.1001256.g005", "stats"=>{"downloads"=>0, "page_views"=>16, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_HNF1_945_is_at_the_heart_of_fucosylation_regulation_/480403", "title"=>"HNF1α is at the heart of fucosylation regulation.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2010-12-23 00:06:43"}
  • {"files"=>["https://ndownloader.figshare.com/files/809518"], "description"=>"<p>Significance plots for regions of interest from the meta-analysis of (a) DG1, (b) DG7 and (c) DG9. A region around the most significant genotyped SNP (represented by a red diamond) is displayed with the –log<sub>10</sub> of the association p-values plotted against chromosome position. The degree of linkage disequilibrium between the most significant SNP and any SNP tested is indicated by a gradient of red shading. Recombination rate is displayed by a blue line with scale on the right-hand axis. Characterized genes in the region are represented with an arrow (showing the direction of transcription). The accompanying association interval as defined in the <a href=\"http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1001256#s4\" target=\"_blank\">methods</a> is marked by vertical red dotted lines.</p>", "links"=>[], "tags"=>["biochemistry/structural genomics", "chemical biology/protein chemistry and proteomics", "genetics and genomics", "genetics and genomics/functional genomics"], "article_id"=>479845, "categories"=>["Biochemistry", "Genetics"], "users"=>["Gordan Lauc", "Abdelkader Essafi", "Jennifer E. Huffman", "Caroline Hayward", "Ana Knežević", "Jayesh J. Kattla", "Ozren Polašek", "Olga Gornik", "Veronique Vitart", "Jodie L. Abrahams", "Maja Pučić", "Mislav Novokmet", "Irma Redžić", "Susan Campbell", "Sarah H. Wild", "Fran Borovecki", "Wei Wang", "Ivana Kolčić", "Lina Zgaga", "Ulf Gyllensten", "James F. Wilson", "Alan F. Wright", "Nicholas D. Hastie", "Harry Campbell", "Pauline M. Rudd", "Igor Rudan"], "doi"=>"https://dx.doi.org/10.1371/journal.pgen.1001256.g001", "stats"=>{"downloads"=>1, "page_views"=>4, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Significance_plots_/479845", "title"=>"Significance plots.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2010-12-23 02:44:05"}
  • {"files"=>["https://ndownloader.figshare.com/files/809821"], "description"=>"<p>A). Real time PCR for <i>HNF1</i>α, <i>HNF4α</i> and <i>FUT6</i> RNAs after <i>HNF1α</i> and <i>HNF4α</i> RNA interference (RNAi) in HepG2 cells. B). Real time PCR for <i>GMDS</i> and <i>L-Fucokinase</i> transcripts after <i>HNF1α</i> and <i>HNF4α</i> RNA interference (RNAi) in HepG2 cells. Expression levels were compared to <i>GAPDH</i> transcripts. All experiments were performed in triplicate. C). Chromatin immunoprecipitation (ChIP) analysis of regions as determined by the indicated primer sets for the <i>GMDS</i> promoter. D). ChIP analysis of regions as determined by the indicated primer sets for the <i>L-Fucokinase</i> promoter and 3′ UTRs. E). ChIP analysis of regions as determined by the indicated primer sets for the <i>HNF4α</i> promoter and 3′ UTRs. F). Reporter activity of the control <i>FUT6</i> promoter upon <i>HNF1α</i> RNAi in HepG2 cells or pcDNA3-HNF1α expression in HEK293 cells. G). Reporter activity of the <i>GMDS</i> and <i>L-Fucokinase</i> promoters upon <i>HNF1α</i> RNAi in HepG2 cells or pcDNA3-HNF1α expression in HEK293 cells. Abbreviations: HNF: Hepatocyte nuclear factor; RNAi: RNA interference, GMDS: GDP-mannose 4,6-dehydratase; L-Fuc: L-Fucokinase; FUT: Fucosyltranferase. 3′UTR: 3′ un-translated region. reChIP: re-precipitation (or sequential) ChIP. See also <a href=\"http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1001256#pgen.1001256.s002\" target=\"_blank\">Figure S2</a> for gene expression results in PANC1 cell line.</p>", "links"=>[], "tags"=>["fucose", "synthesis", "pathway"], "article_id"=>480152, "categories"=>["Biochemistry", "Genetics"], "users"=>["Gordan Lauc", "Abdelkader Essafi", "Jennifer E. Huffman", "Caroline Hayward", "Ana Knežević", "Jayesh J. Kattla", "Ozren Polašek", "Olga Gornik", "Veronique Vitart", "Jodie L. Abrahams", "Maja Pučić", "Mislav Novokmet", "Irma Redžić", "Susan Campbell", "Sarah H. Wild", "Fran Borovecki", "Wei Wang", "Ivana Kolčić", "Lina Zgaga", "Ulf Gyllensten", "James F. Wilson", "Alan F. Wright", "Nicholas D. Hastie", "Harry Campbell", "Pauline M. Rudd", "Igor Rudan"], "doi"=>"https://dx.doi.org/10.1371/journal.pgen.1001256.g003", "stats"=>{"downloads"=>1, "page_views"=>20, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_HNF1_945_is_major_regulator_of_fucose_synthesis_pathway_genes_/480152", "title"=>"HNF1α is major regulator of fucose synthesis pathway genes.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2010-12-23 00:02:32"}
  • {"files"=>["https://ndownloader.figshare.com/files/809938"], "description"=>"<p>Real time PCR for <i>FUT3</i>, <i>FUT5</i> and <i>FUT6</i> RNAs (A); <i>FUT7</i>, <i>FUT9</i>, <i>FUT10</i> and <i>FUT11</i> (B); <i>FUT8</i> (C) after <i>HNF1α</i> and <i>HNF4α</i> RNA interference (RNAi) in HepG2 cells. H) analyses show that Hnf1α (HNF1) and Hnf4α (HNF4) bind predicted regulatory elements for key fucosylation genes in liver cells. D), E), F), G), H) and I) Binding of HNF1α and HNF4α to predicted regulatory elements of the <i>FUT3</i>, <i>FUT5, FUT6, FUT10</i> and <i>FUT11.</i> Abbreviations: the gene names are detailed in <a href=\"http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1001256#pgen-1001256-g001\" target=\"_blank\">Figure 1</a>; P1–P37: Primer sets 1 to 37; 3′UTR: 3′ un-translated region. reChIP: re-precipitation (or sequential) ChIP.</p>", "links"=>[], "tags"=>["fucosyltransferase"], "article_id"=>480276, "categories"=>["Biochemistry", "Genetics"], "users"=>["Gordan Lauc", "Abdelkader Essafi", "Jennifer E. Huffman", "Caroline Hayward", "Ana Knežević", "Jayesh J. Kattla", "Ozren Polašek", "Olga Gornik", "Veronique Vitart", "Jodie L. Abrahams", "Maja Pučić", "Mislav Novokmet", "Irma Redžić", "Susan Campbell", "Sarah H. Wild", "Fran Borovecki", "Wei Wang", "Ivana Kolčić", "Lina Zgaga", "Ulf Gyllensten", "James F. Wilson", "Alan F. Wright", "Nicholas D. Hastie", "Harry Campbell", "Pauline M. Rudd", "Igor Rudan"], "doi"=>"https://dx.doi.org/10.1371/journal.pgen.1001256.g004", "stats"=>{"downloads"=>0, "page_views"=>7, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_HNF1_945_is_major_regulator_of_the_fucosyltransferase_genes_/480276", "title"=>"HNF1α is major regulator of the fucosyltransferase genes.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2010-12-23 00:04:36"}
  • {"files"=>["https://ndownloader.figshare.com/files/404229", "https://ndownloader.figshare.com/files/404246", "https://ndownloader.figshare.com/files/404264", "https://ndownloader.figshare.com/files/404281", "https://ndownloader.figshare.com/files/404324", "https://ndownloader.figshare.com/files/404371"], "description"=>"<div><p>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 (<em>HNF1α</em>) and fucosyltransferase genes <em>FUT6</em> and <em>FUT8</em> 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.</p></div>", "links"=>[], "tags"=>["genomics", "meets", "GWAS", "n-glycome", "identifies", "plasma", "fucosylation"], "article_id"=>139868, "categories"=>["Biochemistry", "Genetics"], "users"=>["Gordan Lauc", "Abdelkader Essafi", "Jennifer E. Huffman", "Caroline Hayward", "Ana Knežević", "Jayesh J. Kattla", "Ozren Polašek", "Olga Gornik", "Veronique Vitart", "Jodie L. Abrahams", "Maja Pučić", "Mislav Novokmet", "Irma Redžić", "Susan Campbell", "Sarah H. Wild", "Fran Borovecki", "Wei Wang", "Ivana Kolčić", "Lina Zgaga", "Ulf Gyllensten", "James F. Wilson", "Alan F. Wright", "Nicholas D. Hastie", "Harry Campbell", "Pauline M. Rudd", "Igor Rudan"], "doi"=>["https://dx.doi.org/10.1371/journal.pgen.1001256.s001", "https://dx.doi.org/10.1371/journal.pgen.1001256.s002", "https://dx.doi.org/10.1371/journal.pgen.1001256.s003", "https://dx.doi.org/10.1371/journal.pgen.1001256.s004", "https://dx.doi.org/10.1371/journal.pgen.1001256.s005", "https://dx.doi.org/10.1371/journal.pgen.1001256.s006"], "stats"=>{"downloads"=>35, "page_views"=>32, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/Genomics_Meets_Glycomics_The_First_GWAS_Study_of_Human_N_Glycome_Identifies_HNF1_as_a_Master_Regulator_of_Plasma_Protein_Fucosylation/139868", "title"=>"Genomics Meets Glycomics—The First GWAS Study of Human N-Glycome Identifies HNF1α as a Master Regulator of Plasma Protein Fucosylation", "pos_in_sequence"=>0, "defined_type"=>4, "published_date"=>"2010-12-23 02:44:28"}
  • {"files"=>["https://ndownloader.figshare.com/files/810187"], "description"=>"<p>*Effect size shown is the β-coefficient, which represents change in glycan levels measured in standard deviation units (after adjustment for covariates) per copy of the allele modelled. NF, non-fucosylated; CF, core fucosylated; AF, antennary fucosylated; See also <a href=\"http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1001256#pgen.1001256.s004\" target=\"_blank\">Tables S1</a> and <a href=\"http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1001256#pgen.1001256.s005\" target=\"_blank\">S2</a>.</p>", "links"=>[], "tags"=>["markers", "plasma", "n-glycan"], "article_id"=>480508, "categories"=>["Biochemistry", "Genetics"], "users"=>["Gordan Lauc", "Abdelkader Essafi", "Jennifer E. Huffman", "Caroline Hayward", "Ana Knežević", "Jayesh J. Kattla", "Ozren Polašek", "Olga Gornik", "Veronique Vitart", "Jodie L. Abrahams", "Maja Pučić", "Mislav Novokmet", "Irma Redžić", "Susan Campbell", "Sarah H. Wild", "Fran Borovecki", "Wei Wang", "Ivana Kolčić", "Lina Zgaga", "Ulf Gyllensten", "James F. Wilson", "Alan F. Wright", "Nicholas D. Hastie", "Harry Campbell", "Pauline M. Rudd", "Igor Rudan"], "doi"=>"https://dx.doi.org/10.1371/journal.pgen.1001256.t001", "stats"=>{"downloads"=>0, "page_views"=>6, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Genetic_markers_associated_with_plasma_N_glycan_levels_/480508", "title"=>"Genetic markers associated with plasma N-glycan levels.", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2010-12-23 00:08:28"}

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Relative Metric

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