1. Gene Aliases

Beta-1,4-Galactosyltransferase 4, Beta4Gal-T4, UDP-Galactose:Beta-N-Acetylglucosamine Beta-1,4-Galactosyltransferase 4, UDP-Gal:BetaGlcNAc Beta 1,4- Galactosyltransferase, Polypeptide 4, UDP-Gal:Beta-GlcNAc Beta-1,4-Galactosyltransferase 4, Lactotriaosylceramide Beta-1,4-Galactosyltransferase, N-Acetyllactosamine Synthase, Beta-1,4-GalTase 4, Nal Synthase, B4Gal-T4, Beta-N-Acetylglucosaminyl-Glycolipid Beta-1,4-Galactosyltransferase 4, Beta-N-Acetylglucosaminyl-Glycolipid Beta-1,4-Galactosyltransferase, UDP-Gal:BetaGlcNAc Beta 1,4- Galactosyltransferase 4, EC 2.4.1.275, BETA4GAL-T4, EC 2.4.1.90, EC 2.4.1.-

[https://www.genecards.org/cgi-bin/carddisp.pl?gene=B4GALT4&keywords=B4galt4]

2. Association with Toxicity and/or Disease at a Transcriptional Level

3. Summary of Protein Family and Structure

4. Proteins Known to Interact with Gene Product

Interactions with experimental support

5. Links to Gene Databases

6. GO Terms, MSigDB Signatures, Pathways Containing Gene with Descriptions of Gene Sets

Pathways:

Glycosaminoglycan metabolism: Glycosaminoglycans (GAGs) are long, unbranched polysaccharides containing a repeating disaccharide unit composed of a hexosamine (either N-acetylgalactosamine (GalNAc) or N-acetylglucosamine (GlcNAc)) and a uronic acid (glucuronate or iduronate). They can be heavily sulfated. GAGs are located primarily in the extracellular matrix (ECM) and on cell membranes, acting as a lubricating fluid for joints and as part of signalling processes. They have structural roles in connective tissue, cartilage, bone and blood vessels (Esko et al. 2009). GAGs are degraded in the lysosome as part of their natural turnover. Defects in the lysosomal enzymes responsible for the metabolism of membrane-associated GAGs lead to lysosomal storage diseases called mucopolysaccharidoses (MPS). MPSs are characterised by the accumulation of GAGs in lysosomes resulting in chronic, progressively debilitating disorders that in many instances lead to severe psychomotor retardation and premature death (Cantz & Gehler 1976, Clarke 2008). The biosynthesis and breakdown of the main GAGs (hyaluronate, keratan sulfate, chondroitin sulfate, dermatan sulfate and heparan sulfate) is described here. [https://reactome.org/PathwayBrowser/#/R-HSA-1630316]

Keratan sulfate biosynthesis: Keratan sulfate (KSI) is the best characterised keratan sulfate. It is 10 times more abundant in cornea than cartilage. KSI is attached to an asparagine (Asn) residue on the core protein via an N-linked branched oligosaccharide (an N-glycan core structure used as a precursor in N-glycan biosynthesis). KSI is elongated by the alternate additions of galactose (Gal) and N-acetylglucosamine (GlcNAc), mediated by glycosyltransferases. Elongation is terminated by the addition of a single N-acetylneuraminic acid (sialyl) residue. KSI is also sulfated on Gal and GlcNAc residues by at least two sulfotransferases (Funderburgh 2000, Funderburgh 2002, Quantock et al. 2010). KSI can be attached to asparagine residues on core proteins, creating so called proteoglycans (PGs). Seven common core proteins found in corneal and skeletal tissues are used as examples here [https://reactome.org/PathwayBrowser/#/R-HSA-2022854].

N-Glycan antennae elongation: N-glycans are further modified after the commitment to Complex or Hybrid N-glycans. The exact structure of the network of metabolic reactions involved is complex and not yet validated experimentally. Here we will show a generic reaction for each of the genes known to be involved in N-Glycosylation.

For a better annotation of the reactions and genes involved in the synthesis of Complex and Hybrid N-glycans we recommend the GlycoGene Database (Ito H. et al, 2010) (http://riodb.ibase.aist.go.jp/rcmg/ggdb/textsearch.jsp) for annotations of genes, and the Consortium for Functional Genomics (http://riodb.ibase.aist.go.jp/rcmg/ggdb/textsearch.jsp) for annotation of Glycan structures and reactions. Moreover, a computationally inferred prediction for the structure of this network is available through the software GlycoVis (Hossler P. et. al. 2006). [https://reactome.org/PathwayBrowser/#/R-HSA-975577]

GO terms:

carbohydrate metabolic process [The chemical reactions and pathways involving carbohydrates, any of a group of organic compounds based of the general formula Cx(H2O)y. GO:0005975]

glycosylation [The covalent attachment and further modification of carbohydrate residues to a substrate molecule. GO:0070085]

keratan sulfate biosynthetic process [The chemical reactions and pathways resulting in the formation of keratan sulfate, a glycosaminoglycan with repeat units consisting of beta-1,4-linked D-galactopyranosyl-beta-(1,4)-N-acetyl-D-glucosamine 6-sulfate and with variable amounts of fucose, sialic acid and mannose units; keratan sulfate chains are covalently linked by a glycosidic attachment through the trisaccharide galactosyl-galactosyl-xylose to peptidyl-threonine or serine residues. GO:0018146]

lactosylceramide biosynthetic process [The chemical reactions and pathways resulting in the formation of lactosylceramides, Gal-beta-(1->4)-Glc-beta(1->1') ceramides, any compound formed by the replacement of the glycosidic C1 hydroxyl group of lactose by a ceramide group. They are the precursors of both gangliosides and globosides. GO:0001572]

protein glycosylation [A protein modification process that results in the addition of a carbohydrate or carbohydrate derivative unit to a protein amino acid, e.g. the addition of glycan chains to proteins. GO:0006486]

MSigDB Signatures:

AMBROSINI_FLAVOPIRIDOL_TREATMENT_TP53: Genes down-regulated by flavopiridol [PubChem=5287969] in the HCT116 cells (colon cancer) depending on their TP53 [GeneID=7157] status: wild-type vs loss of the gene's function (LOF). [https://www.gsea-msigdb.org/gsea/msigdb/human/geneset/AMBROSINI_FLAVOPIRIDOL_TREATMENT_TP53.html]

REACTOME_KERATAN_SULFATE_KERATIN_METABOLISM: Keratan sulfate/keratin metabolism [https://www.gsea-msigdb.org/gsea/msigdb/human/geneset/REACTOME_KERATAN_SULFATE_KERATIN_METABOLISM.html]

KEGG_MEDICUS_REFERENCE_II_BLOOD_GROUP_ANTIGEN_BIOSYNTHESIS: Pathway Definition from KEGG: nLc4Cer -- B3GNT2/3/4 >> B4GALT1/3/4 -> i_antigen -- GCNT2*I -> I_antigen [https://www.gsea-msigdb.org/gsea/msigdb/human/geneset/KEGG_MEDICUS_REFERENCE_II_BLOOD_GROUP_ANTIGEN_BIOSYNTHESIS.html]

KEGG_MEDICUS_REFERENCE_BLOOD_GROUP_H_O_ANTIGEN_TYPE_2_BIOSYNTHESIS: Pathway Definition from KEGG: LacCer -- B3GNT5 >> B4GALT1/2/3/4 -> nLc4Cer -- FUT1H -> TypeIIH // ABOO [https://www.gsea-msigdb.org/gsea/msigdb/human/geneset/KEGG_MEDICUS_REFERENCE_BLOOD_GROUP_H_O_ANTIGEN_TYPE_2_BIOSYNTHESIS.html]

JINESH_BLEBBISHIELD_TRANSFORMED_STEM_CELL_SPHERES_UP: Genes up-regulated in transformed spheres compared to blebbishields from RT4 cells [https://www.gsea-msigdb.org/gsea/msigdb/human/geneset/JINESH_BLEBBISHIELD_TRANSFORMED_STEM_CELL_SPHERES_UP.html]

REACTOME_GLYCOSAMINOGLYCAN_METABOLISM: Glycosaminoglycan metabolism [https://www.gsea-msigdb.org/gsea/msigdb/human/geneset/REACTOME_GLYCOSAMINOGLYCAN_METABOLISM.html]

KEGG_GLYCOSAMINOGLYCAN_BIOSYNTHESIS_KERATAN_SULFATE: Glycosaminoglycan biosynthesis - keratan sulfate [https://www.gsea-msigdb.org/gsea/msigdb/human/geneset/KEGG_GLYCOSAMINOGLYCAN_BIOSYNTHESIS_KERATAN_SULFATE.html]

REACTOME_KERATAN_SULFATE_BIOSYNTHESIS: Keratan sulfate biosynthesis [https://www.gsea-msigdb.org/gsea/msigdb/human/geneset/REACTOME_KERATAN_SULFATE_BIOSYNTHESIS.html]

REACTOME_N_GLYCAN_ANTENNAE_ELONGATION: N-Glycan antennae elongation [https://www.gsea-msigdb.org/gsea/msigdb/human/geneset/REACTOME_N_GLYCAN_ANTENNAE_ELONGATION.html]

REACTOME_POST_TRANSLATIONAL_PROTEIN_MODIFICATION: Post-translational protein modification [https://www.gsea-msigdb.org/gsea/msigdb/human/geneset/REACTOME_POST_TRANSLATIONAL_PROTEIN_MODIFICATION.html]

ACEVEDO_LIVER_TUMOR_VS_NORMAL_ADJACENT_TISSUE_DN: Genes down-regulated in liver tumor compared to the normal adjacent tissue. [https://www.gsea-msigdb.org/gsea/msigdb/human/geneset/ACEVEDO_LIVER_TUMOR_VS_NORMAL_ADJACENT_TISSUE_DN.html]

AMIT_SERUM_RESPONSE_240_MCF10A: Genes whose expression peaked at 240 min after stimulation of MCF10A cells with serum. [https://www.gsea-msigdb.org/gsea/msigdb/human/geneset/AMIT_SERUM_RESPONSE_240_MCF10A.html]

AMIT_SERUM_RESPONSE_480_MCF10A: Genes whose expression peaked at 480 min after stimulation of MCF10A cells with serum. [https://www.gsea-msigdb.org/gsea/msigdb/human/geneset/AMIT_SERUM_RESPONSE_480_MCF10A.html]

PURBEY_TARGETS_OF_CTBP1_NOT_SATB1_UP: Genes up-regulated in HEK-293 cells (fibroblast) upon knockdown of CTBP1 but not of SATB1 [GeneID=1487, 6304] by RNAi. [https://www.gsea-msigdb.org/gsea/msigdb/human/geneset/PURBEY_TARGETS_OF_CTBP1_NOT_SATB1_UP.html]

REACTOME_METABOLISM_OF_CARBOHYDRATES: Metabolism of carbohydrates [https://www.gsea-msigdb.org/gsea/msigdb/human/geneset/REACTOME_METABOLISM_OF_CARBOHYDRATES.html]

ZWANG_CLASS_1_TRANSIENTLY_INDUCED_BY_EGF: Class I of genes transiently induced by EGF [GeneID =1950] in 184A1 cells (mammary epithelium). [https://www.gsea-msigdb.org/gsea/msigdb/human/geneset/ZWANG_CLASS_1_TRANSIENTLY_INDUCED_BY_EGF.html]

7. Gene Descriptions

NCBI Gene Summary: This gene is one of seven beta-1,4-galactosyltransferase (beta4GalT) genes. They encode type II membrane-bound glycoproteins that appear to have exclusive specificity for the donor substrate UDP-galactose; all transfer galactose in a beta1,4 linkage to similar acceptor sugars: GlcNAc, Glc, and Xyl. Each beta4GalT has a distinct function in the biosynthesis of different glycoconjugates and saccharide structures. As type II membrane proteins, they have an N-terminal hydrophobic signal sequence that directs the protein to the Golgi apparatus and which then remains uncleaved to function as a transmembrane anchor. By sequence similarity, the beta4GalTs form four groups: beta4GalT1 and beta4GalT2, beta4GalT3 and beta4GalT4, beta4GalT5 and beta4GalT6, and beta4GalT7. The enzyme encoded by this gene appears to mainly play a role in glycolipid biosynthesis. Two alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Jul 2008]

GeneCards Summary: B4GALT4 (Beta-1,4-Galactosyltransferase 4) is a Protein Coding gene. Diseases associated with B4GALT4 include Ehlers-Danlos Syndrome, Spondylodysplastic Type, 2 and Ehlers-Danlos Syndrome, Spondylodysplastic Type, 1. Among its related pathways are superpathway of glycosphingolipids biosynthesis and Keratan sulfate biosynthesis. Gene Ontology (GO) annotations related to this gene include glycosyltransferase activity and N-acetyllactosamine synthase activity. An important paralog of this gene is B4GALT3.

UniProtKB/Swiss-Prot Summary: Galactose (Gal) transferase involved in the synthesis of terminal N-acetyllactosamine (LacNac) unit present on glycan chains of glycoproteins and glycosphingolipids [PMID: 9792633, PMID: 17690104, PMID: 12511560, PMID: 32827291]. Catalyzes the transfer of Gal residue via a beta1->4 linkage from UDP-Gal to the non-reducing terminal N-acetyl glucosamine 6-O-sulfate (6-O-sulfoGlcNAc) in the linearly growing chain of both N- and O-linked keratan sulfate proteoglycans. Cooperates with B3GNT7 N-acetyl glucosamine transferase and CHST6 and CHST1 sulfotransferases to construct and elongate mono- and disulfated disaccharide units [->3Galbeta1->4(6-sulfoGlcNAcbeta)1->] and [->3(6-sulfoGalbeta)1->4(6-sulfoGlcNAcbeta)1->] within keratan sulfate polymer [PMID: 17690104]. Transfers Gal residue via a beta1->4 linkage to terminal 6-O-sulfoGlcNAc within the LacNac unit of core 2 O-glycans forming 6-sulfo-sialyl-Lewis X (sLex). May contribute to the generation of sLex epitope on mucin-type glycoproteins that serve as ligands for SELL/L-selectin, a major regulator of leukocyte migration [PMID: 12511560]. In the biosynthesis pathway of neolacto-series glycosphingolipids, transfers Gal residue via a beta1->4 linkage to terminal GlcNAc of a lactotriaosylceramide (Lc3Cer) acceptor to form a neolactotetraosylceramide [PMID: 9792633].

8. Cellular Location of Gene Product

Granunlar cytoplasmic expression in most tissues. Localized to the Golgi apparatus. Predicted location: Intracellular [https://www.proteinatlas.org/ENSG00000121578/subcellular]

9. Mechanistic Information

Summary

The B4GALT4 gene encodes a beta-1,4-galactosyltransferase 4 protein, primarily involved in the synthesis of glycan chains on glycoproteins and glycosphingolipids, and contributes to the formation of complex saccharide structures like keratan sulfate. [CS: 9]

The upregulation of B4GALT4 in conditions where the colon is exposed to toxicity or stress, such as in inflammatory diseases, might be a response to facilitate the synthesis and modification of glycoconjugates on cell surfaces, which are crucial for cell-cell communication, adhesion, and immune response modulation. [CS: 8] For instance, the B4GALT4-mediated formation of sLex epitopes on mucin-type glycoproteins serves as ligands for L-selectin, which is significant in regulating leukocyte migration. [CS: 7] This process can be essential in repairing tissue damage or in mediating inflammatory responses. [CS: 8] Additionally, the involvement of B4GALT4 in glycolipid biosynthesis suggests its role in maintaining the integrity of the cell membrane and cellular communication, which are vital under stress conditions in the colon. [CS: 8]

10. Upstream Regulators

11. Tissues/Cell Type Where Genes are Overexpressed

Tissue type enchanced: epididymis (tissue enhanced) [https://www.proteinatlas.org/ENSG00000121578/tissue]

Cell type enchanced: extravillous trophoblasts (cell type enhanced) [https://www.proteinatlas.org/ENSG00000121578/single+cell+type]

12. Role of Gene in Other Tissues

13. Chemicals Known to Elicit Transcriptional Response of Biomarker in Tissue of Interest

Compounds that decrease expression of the gene:

14. DisGeNet Biomarker Associations to Disease in Organ of Interest

No DisGenNet altered expression associations were found for B4galt4 and diseases associated with Colon