Mucin-type O-glycosylation controls pluripotency in mouse embryonic stem cells via Wnt receptor endocytosis
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE152688 | GEO | 2020/06/18
REPOSITORIES: GEO
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Project description:Mucin-type O-glycosylation controls pluripotency in mouse embryonic stem cells via Wnt receptor endocytosis
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Project description:B3GNT7, an important glycosyltransferase highly expressed in intestinal epithelial cells, is involved in physiological processes in the intestine. This study presents novel findings on the potential role and mechanism of B3GNT7 in ulcerative colitis (UC). DSS-induced mouse model of colitis was established to investigate the expression of B3GNT7 in the colon using transcriptomics and immunohistochemistry. Bioinformatics analysis was conducted to explore the biological functions of B3GNT7. The correlation between the transcription levels of B3GNT7 in the colonic tissues of UC patients from the IBDMDB database was analyzed and the severity of colonic inflammation, along with potential mechanisms. The DSS-induced colitis mouse model was successfully established, and transcriptomic analysis revealed a significant downregulation of B3GNT7 expression in the colonic tissues compared to healthy mice. Functional enrichment analysis showed that the main biological function of B3GNT7 was to participate in the mucin O-glycosylation process. Protein interaction analysis indicates that the molecules showing strong interaction with B3GNT7 were members of the mucin MUC family, including MUC2, MUC3, and MUC6. In UC patients, the transcription levels of B3GNT7 were significantly decreased, particularly in patients with moderate to severe disease activity. The expression level of B3GNT7 was negatively correlated with the endoscopic severity of UC. Gene set enrichment analysis (GSEA) further revealed significant enrichment of B3GNT7 in the mucin O-glycosylation synthesis signaling pathway. The downregulation of B3GNT7 expression in the colonic tissues of UC may contribute to impaired mucin barrier function and the progression of colitis.
2024-01-22 | GSE244377 | GEO
Project description:Activation of the Wnt pathway is at the core of many human cancers. During canonical Wnt signaling, the Lrp6 and Frizzled receptors bind to the Wnt growth factor, which leads to the complex being endocytosed. Glycogen Synthase Kinase 3 (GSK3), Dishevelled (Dvl), and Axin are sequestered inside the intraluminal vesicles of late endosomes, known as multivesicular bodies (MVBs). Here we present experiments showing that Wnt causes the endocytosis of focal adhesion (FA) proteins and depletion of Integrin β 1 (ITGβ1) from the cell surface. FAs and integrins provide link the cytoskeleton to the extracellular matrix. Wnt-induced macropinocytosis of the plasma membrane caused ITGβ1 depletion and was accompanied by striking changes in the actin cytoskeleton. In situ protease protection assays in cultured cells showed that ITGβ1 was sequestered within membrane-bounded organelles that corresponded to Wnt-induced MVBs containing GSK3 and focal adhesion-associated proteins. An in vivo model using Xenopus embryos dorsalized by Wnt8 mRNA showed that ITGβ1 depletion decreased Wnt signaling. The cross-talk between Wnt signaling, membrane trafficking, and focal adhesions should be relevant to human cancer and cell biology.
2022-03-18 | GSE193381 | GEO
Project description:Aberrant mucin type O-linked glycosylation is a common occurrence in cancer. This type of O-linked glycosylation can occur on many cell surface glycoproteins where only a small number of sites may be present. EGFR is one such glycoprotein. Upon EGF ligation, EGFR induces a signaling cascade but can also translocate to the nucleus where it can directly regulate gene transcription. Here we show that upon EGF binding, breast cancer cells carrying different O-linked glycans respond by transcribing differential gene expression signatures. This is not a result of changes in signal transduction but due to the differential nuclear translocation of EGFR in the two glyco-phenotypes. This appears to be regulated by the formation of a EGFR/galectin-3/MUC1 complex at the cell surface that is present in cells carrying short core1-based O-glycans characteristic of tumour cells but absent in core 2 O-glycan carrying cells representative of normal mammary epithelial cells.
2020-12-04 | GSE107629 | GEO
Project description:O-linked mucin-type glycosylation regulates the transcriptional programme downstream of EGFR in breast cancer.
| PRJNA420929 | ENA
Project description:Previously, we have identified the polypeptide N-acetylgalactosaminyltransferase 3 (GALNT3) gene as notably hypomethylated in low-malignant potential (LMP) and high-grade (HG) serous epithelial ovarian tumors, compared to normal ovarian tissues. Here we show that GALNT3 is strongly overexpressed in both LMP and HG serous EOC tumors, thus suggesting that epigenetic mechanisms might be implicated in GALNT3 overexpression in serous epithelial ovarian cancer (EOC). Moreover, GALNT3 expression significantly correlated with shorter progression-free survival (PFS) periods in serous EOC patients with advanced disease. Knockdown of the GALNT3 expression in EOC cells led to sharp decrease of cell proliferation and induced S-phase cell cycle arrest. Additionally, GALNT3 suppression significantly inhibited EOC cell migration and invasion. Gene expression profiling and consecutive network and pathway analyses confirmed these findings, as numerous genes and pathways known previously to be implicated in ovarian tumorigenesis, including EOC tumor invasion and metastasis, were found to be downregulated upon GALNT3 suppression, while some tumor suppressor genes were induced. Moreover, GALNT3 downregulation was associated with reduced MUC1 protein expression in EOC cells, probably related to destabilization of the MUC1 protein due to lack of GALNT3 glycosylation activity.Taken together, our data are indicative for a strong oncogenic potential of the GALNT3 gene in advanced EOC and identify this transferase as a novel EOC biomarker and putative EOC therapeutic target. Our findings also suggest that GALNT3 overexpression might contribute to ovarian etiology through aberrant mucin O-glycosylation.
2014-05-22 | GSE52602 | GEO
Project description:Previously, we have identified the polypeptide N-acetylgalactosaminyltransferase 3 (GALNT3) gene as notably hypomethylated in low-malignant potential (LMP) and high-grade (HG) serous epithelial ovarian tumors, compared to normal ovarian tissues. Here we show that GALNT3 is strongly overexpressed in both LMP and HG serous EOC tumors, thus suggesting that epigenetic mechanisms might be implicated in GALNT3 overexpression in serous epithelial ovarian cancer (EOC). Moreover, GALNT3 expression significantly correlated with shorter progression-free survival (PFS) periods in serous EOC patients with advanced disease. Knockdown of the GALNT3 expression in EOC cells led to sharp decrease of cell proliferation and induced S-phase cell cycle arrest. Additionally, GALNT3 suppression significantly inhibited EOC cell migration and invasion. Gene expression profiling and consecutive network and pathway analyses confirmed these findings, as numerous genes and pathways known previously to be implicated in ovarian tumorigenesis, including EOC tumor invasion and metastasis, were found to be downregulated upon GALNT3 suppression, while some tumor suppressor genes were induced. Moreover, GALNT3 downregulation was associated with reduced MUC1 protein expression in EOC cells, probably related to destabilization of the MUC1 protein due to lack of GALNT3 glycosylation activity.Taken together, our data are indicative for a strong oncogenic potential of the GALNT3 gene in advanced EOC and identify this transferase as a novel EOC biomarker and putative EOC therapeutic target. Our findings also suggest that GALNT3 overexpression might contribute to ovarian etiology through aberrant mucin O-glycosylation. To better understand the molecular mechanisms of GALNT3 gene action in ovarian cancer cells, we employed the Agilent Whole Human Genome microarrays, containing ~ 44,000 genes to identify global gene expression changes upon GALNT3 suppression in A2780s cells. We compared the gene expression of the previously selected clone shRNA- GALNT3-knockdown clones 1 & 2 (sh-cl1 & sh-cl2) against the corresponding control (ctrl) clone. The microarray experiments were performed in duplicates, as four hybridizations were carried out for the GALNT3-suppressing cell clones against the corresponding control, using a fluorescent dye reversal (dye-swap) technique.
2014-05-22 | E-GEOD-52602 | biostudies-arrayexpress
Project description:This experiment continues our investigation of glycosylation in endometrial epithelium. During the menstrual cycle, estrogen and progesterone sensitise the uterus to the implanting embryo. There is a major expansion of Golgi and secretory function with increases in mucin (MUC1) and the appearance of specific glycans. We are using Ishikawa cells as a model for in vitro implantation, and have shown the presence of steroid receptors and alterations in glycosylation after hormone exposure.
2011-06-14 | GSE29940 | GEO
Project description:The major focus of Dr. Argueso's research is to characterize the carbohydrate portion of the different mucins expressed by the ocular surface epithelia as well as the enzymes involved with their synthesis, and to determine whether the alteration of mucin glycosylation is associated with ocular surface disease.
2011-03-02 | GSE27593 | GEO
Project description:The densely glycosylated spike (S) proteins that are highly exposed on the surface of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) facilitate viral attachment, entry, and membrane fusion. We have previously reported all the 22 N-glycosites and site-specific N-glycans in the S protein protomer. Herein, we report the comprehensive site-specific O-glycosylation landscapes of SARS-CoV-2 S proteins, which were characterized using high-resolution mass spectrometry. Following digestion using trypsin and trypsin/Glu-C, and de-N-glycosylation using PNGase F, we determined the mucin-type (GalNAc-type) O-glycosylation pattern of S proteins, including O-glycosites and the 6 most common O-glycans occupying them, via Byonic identification and manual validation. Finally, 43 O-glycosites were identified by higher energy collision-induced dissociation (HCD), and 11 O-glycosites were verified by electron transfer/higher energy collision-induced dissociation (EThcD) in the insect cell-expressed S protein. Most glycosites were modified by non-sialylated O-glycans such as HexNAc(1) and HexNAc(1)Hex(1). In contrast, 30 O-glycosites were identified by HCD, and 14 O-glycosites were verified by EThcD in the human cell-expressed S protein S1 subunit. Most glycosites were modified by sialylated O-glycans such as HexNAc(1)Hex(1)NeuAc(1) and HexNAc(1)Hex(1)NeuAc(2). Our results are the first to reveal that the SARS-CoV-2 S protein is a mucin-type glycoprotein; clustered O-glycans often occur in the N- and the C-termini of the S protein, and the O-glycosite and O-glycan compositions vary with the host cell type. These site-specific O-glycosylation landscapes of the SARS-CoV-2 S protein are expected to provide novel insights into the viral binding mechanism and present a strategy for the development of vaccines and targeted drugs.
2021-11-03 | PXD022896 | Pride