Transcriptional regulation of the fucosyltransferase VI gene in hepatocellular carcinoma cells

N‐glycosylation is a ubiquitous protein modification, and N‐glycosylation profiles are emerging as both biomarkers and functional effectors in various types of diabetes. Genome‐wide association studies identified glycosyltransferase genes as candidate causal genes for type 1 and type 2 diabetes. Studies focused on N‐glycosylation changes in type 2 diabetes demonstrated that patients can be distinguished from healthy controls based on N‐glycome composition. In addition, individuals at an increased risk of future disease development could be identified based on N‐glycome profiles. Moreover, accumulating evidence indicates that N‐glycans have a major role in preventing the impairment of glucose‐stimulated insulin secretion by maintaining the glucose transporter in proper orientation, indicating that interindividual variation in protein N‐glycosylation might be a novel risk factor contributing to diabetes development. Defective N‐glycosylation of T cells has been implicated in type 1 diabetes pathogenesis. Furthermore, studies of N‐glycan alterations have successfully been used to identify individuals with rare types of diabetes (such as the HNF1A‐MODY), and also to evaluate functional significance of novel diabetes‐associated mutations. In conclusion, both N‐glycans and glycosyltransferases emerge as potential therapeutic targets in diabetes.

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“…[148][149][150][151][152]. Regulation of transcription activity of the FUT6 gene has also previously been demonstrated for HNF4A [153].…”

Section: Hnf1a Regulates Genes In the Fucosylation Pathwaymentioning

confidence: 61%

Altered N‐glycosylation profiles as potential biomarkers and drug targets in diabetes

2019

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“…This variant, in alternate allelic states, also differentially influences the binding affinity of HNF4α and HNF4γ. HNF4α is a key regulator of FUT6 expression and its knockdown represses the expression of FUT6, and nearby genes FUT3 and FUT5 in HepG2 cell line ( 29 , 30 ). This cluster of FUT genes encodes the α1,3/4 fucosyltransferase family of proteins which add fucose to the GlcNAc moiety in the glycan chain ( 31 ).…”

Section: Discussionmentioning

confidence: 99%

GWAS identifies population-specific new regulatory variants in FUT6 associated with plasma B12 concentrations in Indians

Nongmaithem

Joglekar

Krishnaveni

et al. 2017

Human Molecular Genetics

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Vitamin B12 is an important cofactor in one-carbon metabolism whose dysregulation is associated with various clinical conditions. Indians have a high prevalence of B12 deficiency but little is known about the genetic determinants of circulating B12 concentrations in Indians. We performed a genome-wide association study in 1001 healthy participants in the Pune Maternal Nutrition Study (PMNS), replication studies in 3418 individuals from other Indian cohorts and by meta-analysis identified new variants, rs3760775 (P = 1.2 × 10−23) and rs78060698 (P = 8.3 × 10−17) in FUT6 to be associated with circulating B12 concentrations. Although in-silico analysis replicated both variants in Europeans, differences in the effect allele frequency, effect size and the linkage disequilibrium structure of credible set variants with the reported variants suggest population-specific characteristics in this region. We replicated previously reported variants rs602662, rs601338 in FUT2, rs3760776, rs708686 in FUT6, rs34324219 in TCN1 (all P < 5 × 10−8), rs1131603 in TCN2 (P = 3.4 × 10−5), rs12780845 in CUBN (P = 3.0 × 10−3) and rs2270655 in MMAA (P = 2.0 × 10−3). Circulating B12 concentrations in the PMNS and Parthenon study showed a significant decline with increasing age (P < 0.001), however, the genetic contribution to B12 concentrations remained constant. Luciferase reporter and electrophoretic-mobility shift assay for the FUT6 variant rs78060698 using HepG2 cell line demonstrated strong allele-specific promoter and enhancer activity and differential binding of HNF4α, a key regulator of expression of various fucosyltransferases. Hence, the rs78060698 variant, through regulation of fucosylation may control intestinal host-microbial interaction which could influence B12 concentrations. Our results suggest that in addition to established genetic variants, population-specific variants are important in determining plasma B12 concentrations.

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“…GMDS is involved in the de novo pathway of L-fucose synthesis to produce GDP-fucose, the substrate used by both core and antennary fucosyltransferases to N-glycosylated proteins [24]. Moreover, HNF4α directly regulates the expression of the hepatic fucosyltransferase VI gene ( FUT6 ) [36]. Therefore, we tested whether HNF1α and/or HNF4α might regulate other genes involved in GDP-fucose biosynthesis.…”

Section: Resultsmentioning

confidence: 99%

Genomics Meets Glycomics—The First GWAS Study of Human N-Glycome Identifies HNF1α as a Master Regulator of Plasma Protein Fucosylation

et al. 2010

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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.

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Transcriptional regulation of the fucosyltransferase VI gene in hepatocellular carcinoma cells

Cited by 17 publications

References 40 publications

Altered N‐glycosylation profiles as potential biomarkers and drug targets in diabetes

Altered N‐glycosylation profiles as potential biomarkers and drug targets in diabetes

GWAS identifies population-specific new regulatory variants in FUT6 associated with plasma B12 concentrations in Indians

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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