Global analysis of the interplay between site-specific CREB O-GlcNAc glycosylation and phosphorylation
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA430532 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR6502810.fastq.gz | Fastqsanger.gz | |||
| SRR6502820.fastq.gz | Fastqsanger.gz | |||
| SRR6502811.fastq.gz | Fastqsanger.gz | |||
| SRR6502821.fastq.gz | Fastqsanger.gz | |||
| SRR6502812.fastq.gz | Fastqsanger.gz |
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Project description:Purpose: CREB (cAMP response element binding protein) is a transcription factor that is critical for learning and memory. The activity of CREB is mediated through its post-translational modifications (PTMs); specifically, phosphorylation at serine 133 and glycosylation at serine 40. In this study, we used RNA-Seq and weighted gene network coexpression analysis (WGCNA) to determine the CREB-mediated transcriptional programmes that are regulated by phosphorylation at serine 133 and glycosylation at serine 40 through the use of various PTM-deficient CREB mutants. Methods: The mRNA profiles of E16.5 Creb1-/- mouse cortical neurons expressing GFP, WT CREB, S40A-CREB, S133A-CREB, and S40A-S133A-CREB were generated by deep sequencing, in triplicate, using Illumina HiSeq 2500. The sequence reads that passed quality filters were analyzed using Bowtie, aligned using TopHat, and quantified using Cufflinks in Galaxy. Results: Through differential expression analysis with glycosylation-deficient (S40A) and phosphorylation-deficient (S133A) CREB mutants, we show that CREB O-GlcNAcylation is important for neuronal activity and excitability, while phosphorylation at serine 133 regulates the expression of genes involved in neuronal differentiation. Furthermore, many of the S40A and S133A differentially-expressed genes were directly bound by (1) CREB and its co-activators, CREB-binding protein and p300, (2) activating histone modifications, (3) OGT and O-GlcNAc, and (4) Tet1, an critical regulator of neuronal activity and differentiation. Finally, we observed a positive correlation between S40A and activity- and excitotoxicity-related gene networks and a negative correlation between S133A and neuronal differentiation and amino and fatty acid metabolism-related gene networks. This study demonstrates that CREB O-GlcNAcylation at serine 40 and phosphorylation mediate mutually exclusive gene networks. Together, O-GlcNAc and phosphorylation impart a TF code, which CREB must integrate and decode to modulate neuronal activity, differentiation, and metabolism.
2020-12-17 | GSE109349 | GEO
Project description:Abstract: O-GlcNAc is an abundant post-translational modification found on nuclear and cytoplasmic proteins in all metazoans. This modification regulates a wide variety of cellular processes, and elevated O-GlcNAc levels have been implicated in cancer progression. A single essential enzyme, O-GlcNAc transferase (OGT), is responsible for all nucleocytoplasmic O-GlcNAcylation. Understanding how this enzyme chooses its substrates is critical for understanding, and potentially manipulating, its functions. Here we use protein microarray technology and proteome-wide glycosylation profiling to show that conserved aspartate residues in the tetratricopeptide repeat (TPR) lumen of OGT drive substrate selection. Changing these residues to alanines alters substrate selectivity and unexpectedly increases rates of protein glycosylation. Our findings support a model where sites of glycosylation for many OGT substrates are determined by TPR domain contacts to substrate side chains five to fifteen residues C-terminal to the glycosite. In addition to guiding design of inhibitors that target OGT's TPR domain, this information will inform efforts to engineer substrates to explore biological functions.
2019-07-24 | GSE132205 | GEO
Project description:The combination of CREB inhibitor and JQ1 could overcome the resistance to BET inhibitors in RB loss prostate cancer. Our study firstly showed that GNB1L-CREB pathway was activated after RB loss and considered as the potential target for the prostate cancer therapy
2022-08-30 | GSE191263 | GEO
Project description:Dysfunctional mitochondria and generation of reactive oxygen species (ROS) promote chronic diseases, which have spurred interest in the molecular mechanisms underlying these conditions. Previously, we have demonstrated that disruption of post-translational modification of proteins with β-linked N-acetylglucosamine (O- glcnAcylation) via overexpression of the O-glcnAc–regulating enzymes O- glcnAc transferase (OGT) or O- glcnAcase (OGA) impairs mitochondrial function. Here, we report that sustained alterations in O- glcnAcylation either by pharmacological or genetic manipulation also alters metabolic function. Sustained O-glcnAc elevation in SH-SY5Y neuroblastoma cells increased OGA expression and reduced cellular respiration and ROS generation. Cells with elevated O-glcnAc levels had elongated mitochondria and increased mitochondrial membrane potential, and RNA-Seq in SH-SY5Y cells indicated transcriptome reprogramming and down regulation of the NRF2-mediated antioxidant response. Sustained O-glcnAcylation in mice brain and liver validated the metabolic phenotypes observed in the cells, and OGT knockdown in the liver elevated ROS levels, impaired respiration, and increased the NRF2 antioxidant response. Moreover, elevated O-glcnAc levels promoted weight loss and lowered respiration in mice and skewed the mice toward carbohydrate-dependent metabolism as determined by indirect calorimetry. In summary, sustained elevation in O-glcnAcylation coupled with increased OGA expression reprograms energy metabolism, a finding that has potential implications for the etiology, development, and management of metabolic diseases.
2017-07-20 | GSE101642 | GEO
Project description:Hepatocarcinoma is the third leading cause of death in cancer in the world. In recent years, research on CREB in hepatocellular carcinoma has become a hotspot, so our research group wants to use the mass spectrometry analysis what proteins can bind with CREB, and then explore the links between CREB and hepatocellular carcinoma.
2019-11-08 | PXD008261 | Pride
Project description:Tissue fibrosis is induced by chronic inflammation accompanied by repeated injuries. Chronic inflammation alters fibroblasts and stellate cells, maintaining the tissues in myofibroblasts and activating stellate cells. This activation promotes the augmentation of these cells and the abundant production of extracellular matrices, such as collagen. Fibrotic tissue dysfunction is eventually induced by expelling parenchymal cells with these abundant collagen depositions. To recover from tissue fibrosis, the activation of myofibroblasts and stellate cells is suppressed by selectively targeting these cells. Here we show that O-N-acetylglucosamine (GlcNAc)-modified proteins leaked from dead cells and GlcNAc-bearing polymers mimicking the GlcNAc moiety of these proteins suppress the activation of these cells; administration of the GlcNAc-bearing polymer into carbon tetrachloride-treated mice can improve liver fibrosis. We found that a multivalent GlcNAc moiety structure elicited antifibrotic activities in myofibroblasts by interacting with cell surface vimentin and desmin. Therefore, since these cells highly express cytoskeletal proteins, vimentin and desmin, on the cell surface and have GlcNAc-binding activity, we suggest that O-GlcNAc-modified proteins leaked from dead cells can function as suppressors of fibrosis and hyperplasia in spontaneous recovery. Moreover, we anticipate that GlcNAc-bearing polymers mimicked by O-GlcNAc-modified proteins will be useful as new therapeutic tools for fibrosis and hyperplasia.
2022-03-30 | GSE199656 | GEO
Project description:Heparan sulfate (HS), a long linear polysaccharide, is implicated in various steps of tumorigenesis, including angiogenesis. We successfully interfered with HS biosynthesis using a peracetylated 4-deoxy analog of the HS constituent GlcNAc and studied the compoundM-bM-^@M-^Ys metabolic fate and its effect on angiogenesis. The 4-deoxy analog was activated intracellularly into UDP-4-deoxy-GlcNAc and HS expression was inhibited up to ~96% (IC50 = 16 M-BM-5M). HS chain size was reduced, without detectable incorporation of the 4-deoxy analog, likely due to reduced levels of UDP-GlcNAc and/or inhibition of glycosyltransferase activity. Comprehensive gene expression analysis revealed reduced expression of genes regulated by HS binding growth factors as FGF-2 and VEGF. Cellular binding and signaling of these angiogenic factors was inhibited. Micro-injection in zebrafish embryos strongly reduced HS biosynthesis, and angiogenesis was inhibited in both zebrafish and chicken model systems. All these data identify 4-deoxy-GlcNAc as a potent inhibitor of HS synthesis which hampers pro-angiogenic signaling and neo-vessel formation. 9 samples were analyzed: 3 biological replicates from untreated SKOV3 cells, 3 biological replicates from SKOV3 cells treated with peracetylated GlcNAc, 3 biological replicates from SKOV3 cells treated with peracetylated 4-deoxy-GlcNAc
2013-08-23 | E-GEOD-48284 | biostudies-arrayexpress
Project description:Beauveria bassiana is a popular and eco-friendly biopesticide. Sensing N-acetylglucosamine (GlcNAc) , a building block of both insect exoskeleton and fungal cell wall, might play a vital role during B. bassiana pathogen-pest interaction. Previous studies in Candida albicans have demonstrated that a GlcNAc sensor (termed as Ngs1) was in response to GlcNAc signal sensing and transportation. Herein, we found a Ngs1 homology in B. bassiana, and reported the alteration of transcriptomic profiles between wild-type strain and Ngs1-deletion mutants grown on cuticle broth (CB) supplemented with 1% cuticle powder of Locusta migratoria exoskeleton, followed by shaking at 150 rpm for 5 days at 25 ℃.
2024-05-31 | GSE267338 | GEO
Project description:Our goal is to understand how glycosylation on human B cells is regulated during the differentiation and activation. Accumulating evidences have indicated that functions of immune cells are regulated in a glycan-dependent manner. One of well-known examples is B cell regulation by CD22 through its association with sialylated glycans. While recent studies uncovered that B cell activation leads to loss of high affinity glycan ligands for human CD22 (Neu5Ac-a2,6-Gal-B1,4-GlcNAc(6-sulfo)), the gene expression profile of human B cells before and after activation is unknown. Therefore we would like to perform gene expression analysis of human B cells before and after activation. We already have published the glycan profiling and gene expression of mouse B cells before and after activation done in collaboration with the CFG. This study revealed programmed changes in glycosylation relevant to regulation of B cell signaling by CD22. Since the ligands of human CD22 differ in several respects from that of mouse CD22, these experiments are relevant to the evolution of siglec ligands and their conserved functions in B cell biology.
2011-09-06 | GSE31932 | GEO
Project description:HIV-associated neurocognitive disorders (HAND) remain an unsolved problem that persists despite using antiretroviral therapy. We have obtained data showing that HIV-gp120 protein contributes to neurodegeneration through metabolic reprogramming. This led to decreased ATP levels, lower mitochondrial DNA copy numbers, and loss of mitochondria cristae, all-important for mitochondrial biogenesis. gp120 protein also disrupted mitochondrial movement and synaptic plasticity. Searching for the mechanisms involved, we found that gp120 alters the cyclic AMP response element-binding protein (CREB) phosphorylation on serine residue 133 necessary for its function as a transcription factor. Since CREB regulates the promoters of PGC1 and BDNF genes, we found that CREB dephosphorylation causes PGC1 and BDNF loss of functions. Our data was validated in vitro and in vivo. The negative effect of gp120 was alleviated in cells and animals in the presence of rolipram that inhibits the phosphodiesterase protein 4 (PDE4) and restores CREB phosphorylation. We concluded that HIV-gp120 protein contributes to HAND via inhibition of CREB protein function.
2022-06-09 | PXD031891 | Pride