Genomics meets glycomics-the first GWAS study of human N-Glycome identifies HNF1α as a master regulator of plasma protein fucosylation.
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 process...
Saved in:
| Main Authors: | , , , , , , , , , , , , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Public Library of Science (PLoS)
2010-12-01
|
| Series: | PLoS Genetics |
| Online Access: | https://journals.plos.org/plosgenetics/article/file?id=10.1371/journal.pgen.1001256&type=printable |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1850236730401095680 |
|---|---|
| author | 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 Borovečki Wei Wang Ivana Kolčić Lina Zgaga Ulf Gyllensten James F Wilson Alan F Wright Nicholas D Hastie Harry Campbell Pauline M Rudd Igor Rudan |
| author_facet | 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 Borovečki Wei Wang Ivana Kolčić Lina Zgaga Ulf Gyllensten James F Wilson Alan F Wright Nicholas D Hastie Harry Campbell Pauline M Rudd Igor Rudan |
| author_sort | Gordan Lauc |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-0bedf96abf874f8498dbe8e95fd5af17 |
| institution | OA Journals |
| issn | 1553-7390 1553-7404 |
| language | English |
| publishDate | 2010-12-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS Genetics |
| spelling | doaj-art-0bedf96abf874f8498dbe8e95fd5af172025-08-20T02:01:54ZengPublic Library of Science (PLoS)PLoS Genetics1553-73901553-74042010-12-01612e100125610.1371/journal.pgen.1001256Genomics meets glycomics-the first GWAS study of human N-Glycome identifies HNF1α as a master regulator of plasma protein fucosylation.Gordan LaucAbdelkader EssafiJennifer E HuffmanCaroline HaywardAna KneževićJayesh J KattlaOzren PolašekOlga GornikVeronique VitartJodie L AbrahamsMaja PučićMislav NovokmetIrma RedžićSusan CampbellSarah H WildFran BorovečkiWei WangIvana KolčićLina ZgagaUlf GyllenstenJames F WilsonAlan F WrightNicholas D HastieHarry CampbellPauline M RuddIgor RudanOver 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.https://journals.plos.org/plosgenetics/article/file?id=10.1371/journal.pgen.1001256&type=printable |
| spellingShingle | 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 Borovečki Wei Wang Ivana Kolčić Lina Zgaga Ulf Gyllensten James F Wilson Alan F Wright Nicholas D Hastie Harry Campbell Pauline M Rudd Igor Rudan Genomics meets glycomics-the first GWAS study of human N-Glycome identifies HNF1α as a master regulator of plasma protein fucosylation. PLoS Genetics |
| title | Genomics meets glycomics-the first GWAS study of human N-Glycome identifies HNF1α as a master regulator of plasma protein fucosylation. |
| title_full | Genomics meets glycomics-the first GWAS study of human N-Glycome identifies HNF1α as a master regulator of plasma protein fucosylation. |
| title_fullStr | Genomics meets glycomics-the first GWAS study of human N-Glycome identifies HNF1α as a master regulator of plasma protein fucosylation. |
| title_full_unstemmed | Genomics meets glycomics-the first GWAS study of human N-Glycome identifies HNF1α as a master regulator of plasma protein fucosylation. |
| title_short | Genomics meets glycomics-the first GWAS study of human N-Glycome identifies HNF1α as a master regulator of plasma protein fucosylation. |
| title_sort | genomics meets glycomics the first gwas study of human n glycome identifies hnf1α as a master regulator of plasma protein fucosylation |
| url | https://journals.plos.org/plosgenetics/article/file?id=10.1371/journal.pgen.1001256&type=printable |
| work_keys_str_mv | AT gordanlauc genomicsmeetsglycomicsthefirstgwasstudyofhumannglycomeidentifieshnf1aasamasterregulatorofplasmaproteinfucosylation AT abdelkaderessafi genomicsmeetsglycomicsthefirstgwasstudyofhumannglycomeidentifieshnf1aasamasterregulatorofplasmaproteinfucosylation AT jenniferehuffman genomicsmeetsglycomicsthefirstgwasstudyofhumannglycomeidentifieshnf1aasamasterregulatorofplasmaproteinfucosylation AT carolinehayward genomicsmeetsglycomicsthefirstgwasstudyofhumannglycomeidentifieshnf1aasamasterregulatorofplasmaproteinfucosylation AT anaknezevic genomicsmeetsglycomicsthefirstgwasstudyofhumannglycomeidentifieshnf1aasamasterregulatorofplasmaproteinfucosylation AT jayeshjkattla genomicsmeetsglycomicsthefirstgwasstudyofhumannglycomeidentifieshnf1aasamasterregulatorofplasmaproteinfucosylation AT ozrenpolasek genomicsmeetsglycomicsthefirstgwasstudyofhumannglycomeidentifieshnf1aasamasterregulatorofplasmaproteinfucosylation AT olgagornik genomicsmeetsglycomicsthefirstgwasstudyofhumannglycomeidentifieshnf1aasamasterregulatorofplasmaproteinfucosylation AT veroniquevitart genomicsmeetsglycomicsthefirstgwasstudyofhumannglycomeidentifieshnf1aasamasterregulatorofplasmaproteinfucosylation AT jodielabrahams genomicsmeetsglycomicsthefirstgwasstudyofhumannglycomeidentifieshnf1aasamasterregulatorofplasmaproteinfucosylation AT majapucic genomicsmeetsglycomicsthefirstgwasstudyofhumannglycomeidentifieshnf1aasamasterregulatorofplasmaproteinfucosylation AT mislavnovokmet genomicsmeetsglycomicsthefirstgwasstudyofhumannglycomeidentifieshnf1aasamasterregulatorofplasmaproteinfucosylation AT irmaredzic genomicsmeetsglycomicsthefirstgwasstudyofhumannglycomeidentifieshnf1aasamasterregulatorofplasmaproteinfucosylation AT susancampbell genomicsmeetsglycomicsthefirstgwasstudyofhumannglycomeidentifieshnf1aasamasterregulatorofplasmaproteinfucosylation AT sarahhwild genomicsmeetsglycomicsthefirstgwasstudyofhumannglycomeidentifieshnf1aasamasterregulatorofplasmaproteinfucosylation AT franborovecki genomicsmeetsglycomicsthefirstgwasstudyofhumannglycomeidentifieshnf1aasamasterregulatorofplasmaproteinfucosylation AT weiwang genomicsmeetsglycomicsthefirstgwasstudyofhumannglycomeidentifieshnf1aasamasterregulatorofplasmaproteinfucosylation AT ivanakolcic genomicsmeetsglycomicsthefirstgwasstudyofhumannglycomeidentifieshnf1aasamasterregulatorofplasmaproteinfucosylation AT linazgaga genomicsmeetsglycomicsthefirstgwasstudyofhumannglycomeidentifieshnf1aasamasterregulatorofplasmaproteinfucosylation AT ulfgyllensten genomicsmeetsglycomicsthefirstgwasstudyofhumannglycomeidentifieshnf1aasamasterregulatorofplasmaproteinfucosylation AT jamesfwilson genomicsmeetsglycomicsthefirstgwasstudyofhumannglycomeidentifieshnf1aasamasterregulatorofplasmaproteinfucosylation AT alanfwright genomicsmeetsglycomicsthefirstgwasstudyofhumannglycomeidentifieshnf1aasamasterregulatorofplasmaproteinfucosylation AT nicholasdhastie genomicsmeetsglycomicsthefirstgwasstudyofhumannglycomeidentifieshnf1aasamasterregulatorofplasmaproteinfucosylation AT harrycampbell genomicsmeetsglycomicsthefirstgwasstudyofhumannglycomeidentifieshnf1aasamasterregulatorofplasmaproteinfucosylation AT paulinemrudd genomicsmeetsglycomicsthefirstgwasstudyofhumannglycomeidentifieshnf1aasamasterregulatorofplasmaproteinfucosylation AT igorrudan genomicsmeetsglycomicsthefirstgwasstudyofhumannglycomeidentifieshnf1aasamasterregulatorofplasmaproteinfucosylation |