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Inhibition of O-GlcNAcylation via O-GlcNAc transferase fosters megakaryopoiesis and induces thrombopoiesis

ABSTRACT: Inhibition of O-GlcNAcylation via O-GlcNAc transferase fosters megakaryopoiesis and induces thrombopoiesis

PROVIDER: PRJNA633908 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR11814500_1.fastq.gz	Fastqsanger.gz
	SRR11814500_2.fastq.gz	Fastqsanger.gz
	SRR11814497_1.fastq.gz	Fastqsanger.gz
	SRR11814497_2.fastq.gz	Fastqsanger.gz
	SRR11814498_1.fastq.gz	Fastqsanger.gz

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Similar Datasets

Inhibition of O-GlcNAcylation via O-GlcNAc transferase fosters megakaryopoiesis and induces thrombopoiesis

Project description:We report that cellular O-GlcNAcylation levels decline along the course of megakaryocyte (MK) differentiation from human-derived hematopoietic stem and progenitor cells (HSPCs) and that inhibition of O-GlcNAc transferase (OGT), of which catalyzes O-GlcNAcylation, prolongedly decreases O-GlcNAcylation and induces megakaryopoiesis and thrombopoiesis. To gain the better insight into the potential mechanisms underlying platelet regulation by O-GlcNAcylation ,we compared the genome-wide transcription profiles of megakaryblastic MEG-01 cells with decreased O-GlcNAcylation (OGTi) and its control counterpart using RNA sequencing. Gene ontology and enrichment analysis of differentially expressed genes suggest that platelet formation might be regulated through the perturbation in cell adhesion molecules, i.e. integrin-a4 and b7, downstream of O-GlcNAc/c-Myc axis.

2020-08-06 | GSE150880 | GEO

Metabolic sensor O-GlcNAcylation regulates megakaryopoiesis and thrombopoiesis through c-Myc stabilization and integrin perturbation.

Project description:Metabolic state of hematopoietic stem cells (HSCs) is an important regulator of self-renewal and lineage-specific differentiation. Posttranslational modification of proteins via O-GlcNAcylation is an ideal metabolic sensor, but how it contributes to megakaryopoiesis and thrombopoiesis remains unknown. Here, we reveal for the first time that cellular O-GlcNAcylation levels decline along the course of megakaryocyte (MK) differentiation from human-derived hematopoietic stem and progenitor cells (HSPCs). Inhibition of O-GlcNAc transferase (OGT) that catalyzes O-GlcNAcylation prolongedly decreases O-GlcNAcylation and induces the acquisition of CD34+ CD41a+ MK-like progenitors and its progeny CD34- CD41a+ /CD42b+ megakaryoblasts (MBs)/MKs from HSPCs, consequently resulting in increased CD41a+ and CD42b+ platelets. Using correlation and co-immunoprecipitation analyses, we further identify c-Myc as a direct downstream target of O-GlcNAcylation in MBs/MKs and provide compelling evidence on the regulation of platelets by novel O-GlcNAc/c-Myc axis. Our data indicate that O-GlcNAcylation posttranslationally regulates c-Myc stability by interfering with its ubiquitin-mediated proteasomal degradation. Depletion of c-Myc upon inhibition of OGT promotes platelet formation in part through the perturbation of cell adhesion molecules, that is, integrin-α4 and integrin-β7, as advised by gene ontology and enrichment analysis for RNA sequencing and validated herein. Together, our findings provide a novel basic knowledge on the regulatory role of O-GlcNAcylation in megakaryopoiesis and thrombopoiesis that could be important in understanding hematologic disorders whose etiology are related to impaired platelet production and may have clinical applications toward an ex vivo platelet production for transfusion.

| S-EPMC8248081 | biostudies-literature

selective protein O-glcNAcylation in cells by a proximity-directed O-GlcNAc transferase

Project description:O-Linked N-acetylglucosamine (O-GlcNAc) is a monosaccharide that plays an essential role in cellular signaling throughout the nucleocytoplasmic proteome of eukaryotic cells. Yet, the study of post-translational modifications like O-GlcNAc has been limited by the lack of strategies to induce O-GlcNAcylation of a target protein in cells. Here, we report a generalizable genetic strategy to induce O-GlcNAc to specific target proteins in cells using a nanobody as a proximity-directing agent fused to O-GlcNAc transferase (OGT). Fusion of a nanobody that recognizes GFP (nGFP) or a nanobody that recognizes the four-amino acid sequence EPEA (nEPEA) to OGT(4), a truncated form of OGT, yielded a nanobody-OGT(4) construct that selectively delivered O-GlcNAc to the target protein (e.g., JunB, cJun, Nup62) and reduced alteration of global O-GlcNAc levels in the cell. Chemical proteomics confirmed the selective increase in O-GlcNAc to the target protein by nanobody-OGT(4). Glycoproteomics on the target protein revealed similar glycosite selectivity between nanobody-OGT(4) or global elevation of O-GlcNAc. Finally, we demonstrate the ability to selectively target endogenous ⍺-synuclein for glycosylation in HEK293T cells. Thus, the use of nanobodies to redirect OGT substrate selection is a versatile strategy to induce glycosylation to desired target proteins in cells that will facilitate discovery of O-GlcNAc functions and provide a mechanism to engineer O-GlcNAc signaling. The proximity-directed OGT approach for protein-selective O-GlcNAcylation is readily translated to additional protein targets and nanobodies, and may constitute a generalizable strategy to control post-translational modifications in cells.

2021-09-08 | PXD016041 | Pride

Caulis Polygoni Multiflori accelerates megakaryopoiesis and thrombopoiesis via activating PI3K/Akt and MEK/ERK (MAPK) signaling pathways

Project description:Caulis Polygoni Multiflori accelerates megakaryopoiesis and thrombopoiesis via activating PI3K/Akt and MEK/ERK (MAPK) signaling pathways

| PRJNA874815 | ENA

Effect of O-GlcNAc transferase deficiency on intestinal epithelial cells in mice

Project description:O-GlcNAcylation is the modification of serine and threonine residues with beta-N-acetylglucosamine (O-GlcNAc) on intracellular proteins. To investigate the role of protein O-GlcNAcylation on intestinal homeostasis, we generated intestinal epithelial cell (IEC)-specific O-GlcNAc transferase (OGT) knockout in mice. The KO mice developed spontanous intestinal inflammation. To determine the underlying molecular mechanisms, we performed RNA sequencing of ileum and colon epithelial cells of wildtype and IEC-OGT KO mice.

2017-06-27 | GSE100473 | GEO

RNA Sequencing of HEK293T cells expressing a Dual-specificity Aptamer that specifically increases O-GlcNAcylation on beta-catenin when O-GlcNAc transferase was inhibited

Project description:O-GlcNAc is a dynamic post-translational modification on thousands of intracellular proteins, it regulates protein functions and is involved in many metabolic diseases. Using a dual-specificity aptamer, we targeted the O-GlcNAc transferase (OGT) to endogenous β-catenin and specifically increased O-GlcNAcylation of β-catenin. To study how O-GlcNAcylation of β-catenin regulates the transcriptome, we performed RNA sequencing on HEK293T cells expressing individual (Ctrl.) or dual-specificity aptamers. We found that O-GlcNAcylation of β-catenin shifts the transcriptome in a Wnt-dependent manner: it repressed the expression of about 100 genes in the absence of Wnt, while it activated the expression of these genes when Wnt signaling was turned on. This dataset is from the control experiment in which all samples were treated with the OGT inhibitor Ac5S.

2022-11-01 | GSE189622 | GEO

YAP1 regulates thrombopoiesis by binding to MYH9 in immune thrombocytopenia

Project description:Immune thrombocytopenia (ITP) is a complicated bleeding disease characterized by sharp platelet reduction. As a dominating element involved in ITP, megakaryocytes (MKs) are responsible for thrombopoiesis. However, the mechanism behind the dysregulation of thrombopoiesis in ITP remains undetermined. In this study, we examined the role of YAP1, Yes-associated protein 1, in thrombopoiesis during ITP. We observed a reduced YAP1 expression with cytoskeletal actin misalignment in MKs of ITP patients. Using experimental ITP mice, we showed that YAP1 reduction induced aberrant MK distribution, reduced the percentage of late MKs in total MKs, and caused submaximal platelet recovery. Mechanistically, YAP1 upregulation by GATA1 binding to its promoter promoted MK maturation. Phosphorylated YAP1 facilitated cytoskeletal activation by binding of its WW2 domain to MYH9, facilitating thrombopoiesis. Targeting YAP1 by its activator XMU-MP-1 was sufficient to rescue cytoskeleton defects and thrombopoiesis in YAP1+/- ITP mice and ITP patients. Taken together, these results demonstrate a crucial role for YAP1 in thrombopoiesis, providing a potential for the development of diagnostic markers and therapeutic options for ITP.

2024-12-22 | GSE250220 | GEO

CUT&RUN Sequencing of EZH2 binding sites in HEK293T cells expressing a Dual-specificity Aptamer that specifically increases O-GlcNAcylation on beta-catenin when O-GlcNAc transferase was inhibited

Project description:O-GlcNAc is a dynamic post-translational modification on thousands of intracellular proteins, it regulates protein functions and is involved in many metabolic diseases. Using a dual-specificity aptamer, we targeted the O-GlcNAc transferase (OGT) to endogenous β-catenin and specifically increased O-GlcNAcylation of β-catenin. We found that O-GlcNAc on β-catenin promoted its interaction with EZH2 regardless of the Wnt signaling status. To study how this interaction regulates the distribution of EZH2 on the genome, we performed Cleavage Under Targets and Release Using Nuclease (CUT&RUN) on HEK293T cells expressing individual (Ctrl.) or dual-specificity aptamers, under Wnt - and Wnt + conditions. This is a control experiment in which all samples were treated with the OGT inhibitor Ac5S.

2022-10-11 | GSE214774 | GEO

Single cell RNA sequencing on chronic deletion of hepatic O-GlcNAc Transferase in mice

Project description:Single cell RNA sequencing, 5 week deletion of O-GlcNAc transferase (OGT) in hepatocytes

2023-11-08 | GSE223830 | GEO

Conserved nutrient sensor O-GlcNAc transferase is integral to the C. elegans pathogen-specific immune response

Project description:Discriminating pathogenic bacteria from energy-harvesting commensals is key to host immunity. Using mutants defective in the enzymes of O-linked N-acetylglucosamine (O-GlcNAc) cycling, we examined the role of this nutrient-sensing pathway in the Caenorhabidits elegans innate immune response. Using whole genome transcriptional profiling, O-GlcNAc cycling mutants exhibited deregulation of unique stress- and immune-responsive genes as well as genes shared with the p38 MAPK/PMK-1 pathway. Moreover, genetic analysis showed that deletion of O-GlcNAc transferase (ogt-1) yielded animals hypersensitive to the human pathogen S. aureus but not to P. aeruginosa. Genetic interaction studies further revealed that nutrient-responsive OGT-1 acts through the conserved ß-catenin (BAR-1) pathway and in concert with p38 MAPK/PMK-1 to modulate the immune response to S. aureus. The participation of the nutrient sensor O-GlcNAc transferase in an immunity module conserved from C. elegans to humans reveals an unexplored nexus between nutrient availability and a pathogen-specific immune response. In C. elegans, three mutant strains(genotypes used: N2 (wild-type), ogt-1 (ok1474), oga-1 (ok1207), and pmk-1 (km25)) were treated with the human pathogen S. aureus (SA) or P. aeruginosa(PA) and OP50 (E. coli control) with three biological replications.

2015-05-01 | E-GEOD-53732 | biostudies-arrayexpress

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