Reversible Histone Glycation Drives Disease-Associated Changes in Chromatin Architecture
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE121252 | GEO | 2019/02/14
REPOSITORIES: GEO
Similar Datasets
Project description:Reversible Histone Glycation Drives Disease-Associated Changes in Chromatin Architecture
| PRJNA496485 | ENA
Project description:Reactive cellular metabolites can modify macromolecules and form adducts known as non-enzymatic covalent modifications (NECMs). Dissecting the mechanisms, regulation and consequences of NECMs, such as glycation, has been challenging due to the complex and often ambiguous nature of the adducts formed. Directly tracking the formation of modifications on key targets to uncover their underlying physiological importance requires specific chemical tools. Here we present the novel chemoenzymatic syntheses of an active azido-modified ribose analog, 5-azidoribose (5-AR), as well as an inactive control derivative, 1-azidoribose (1-AR) and their application towards understanding protein ribose-glycation in vitro and in cellulo. With these new probes we found that, similar to MGO-glycation, ribose glycation specifically accumulates on histones. In addition to fluorescent labeling, we demonstrate the utility of the probe in enriching modified targets, which were identified by label-free quantitative proteomics and highresolution MS/MS workflows. Finally, we establish that the known oncoprotein and hexose deglycase, fructosamine 3-kinase (FN3K), recognizes and facilitates the removal of 5-AR glycation adducts in live cells, supporting the dynamic regulation of ribose glycation as well as validating the probe as a new chemical tool to monitor FN3K activity. Altogether, we demonstrate this probe’s utilities to uncover ribose-glycation and deglycation events as well as tracking FN3K activity towards establishing its potential as a new cancer vulnerability.
2020-05-15 | PXD019204 | Pride
Project description:We performed bulk transcriptomic analysis to examine how glycation-modified collagen further impacts the function of meningeal fibroblasts. We preprocessed raw data to align bulk RNA-seq using STAR (detailed in Experimental Section) and identified differentially expressed genes (DEGs), especially ECM-related gene sets.
2022-10-26 | GSE216298 | GEO
Project description:We show that NRF2 activation drives hepatocellular carcinoma development in vivo. Moreover, NRF2 undergoes glucose dependent modification called glycation and requires the de-glycating enzyme FN3K to maintain NRF2' oncogenic functions.
2019-06-22 | GSE133160 | GEO
Project description:Understanding the effect of glycation on the function of transferrin, the systemic iron transporter, is fundamental to fully grasp the mechanisms leading to the loss of iron homeostasis observed in diabetes mellitus (DM). The spontaneous reaction with protein amino groups is one of the main causes of glucose toxicity, but the site specificity of this reaction is still poorly understood. Unbalance of iron metabolism has long been described in DM patients, and one of the main features is the occurrence of non-transferrin-bound iron in the blood serum. The presence of these toxic iron species is observed, despite low transferrin saturation levels. Here in, an in vitro approach was used to study human holo-transferrin glycation in detail. Holo-transferrin was incubated with increasing concentration of glucose (10; 20; 100 and 500 mM) and glycation sites were identified using nano-reverse phase – liquid chromatography coupled to high resolution mass spectrometry (nLC-MS). Overall 21 glycation hotspots were identified with lysine residues 103, 312 and 380 proving to be the most reactive sites. Glycation specificity was found to be remarkably different from that described for apo-transferrin.
2018-05-30 | PXD009345 | Pride
Project description:Glycation is a post-translational modification underlied by the interaction of protein amino and guanidino groups with carbonyl compounds like reducing sugars and α-dicarbonyls. In the first steps of this process, the protein amino groups react with reducing carbohydrates yielding the corresponding keto- and aldimines, i.e. Amadori and Heyns compounds, respectively. Further degradation of these products results in the formation of advanced glycation end products (AGEs). Alternatively, some representatives of this heterogeneous compound group can originate from α-dicarbonyl products of monosaccharide autoxidation or primary cellular metabolism. In mammals, AGEs are continuously formed during the life of the organism, and accumulate in the tissues, being well-known markers of ageing and impacting age-related stiffing of tissues, decrease of muscle performance, and atherosclerotic changes. However, although the role of AGEs in the ageing of animal tissues is well-studied, their impact in the age-related molecular alterations in plants is completely unknown. To fill this gap, we present here a comprehensive study of the age-related changes in the plant glycated proteome in terms of affected proteins and individual glycation sites therein. Thereby, we consider the qualitative and quantitative changes in glycation patterns in terms of the general metabolic background, pathways of AGE formation, and the status of plant anti-oxidative/anti-glycative defense. Although the patterns of glycated proteins were only minimally influenced by plant age, the abundances of 96 advanced glycation sites in 71 proteins were significantly affected in an age-dependent manner and clearly indicate the existence of glycation hotspots in the plant proteome, the nature of which is discussed here in the sense of structural considerations.
2017-06-19 | PXD006434 | Pride
Project description:Ossification of the posterior longitudinal ligament (OPLL) is formed by heterogeneous ossification of posterior longitudinal ligament. The patho-mechanism of OPLL is still largely unknown. Recently, disorders of metabolism are thought to be the center of many diseases such as OPLL. Advanced glycation end product (AGE) are accumulated in many extracellular matrixes such as ligament fibers, and it can functions as cellular signal through its receptor (RAGE), contributing to various events such as atherosclerosis or oxidative stress. However, its role in OPLL formation is not yet known. Therefore, we performed high-through-put RNA sequencing on primary posterior longitudinal ligament cells treated with different doses of AGEs (1µM, 5µM and negative control), with or without BMP2 (1µM). mRNA profiles of Primary human posterior longitudinal ligament cells stimulated with various stimuli (Control, 1µM AGE-BSA, 5µM AGE-BSA, 1µM AGE-BSA with BMP2, 5µM AGE-BSA with BMP2) were generated by deep sequencing on Ion Proton
2016-02-16 | E-GEOD-65952 | biostudies-arrayexpress
Project description:Ossification of the posterior longitudinal ligament (OPLL) is formed by heterogeneous ossification of posterior longitudinal ligament. The patho-mechanism of OPLL is still largely unknown. Recently, disorders of metabolism are thought to be the center of many diseases such as OPLL. Advanced glycation end product (AGE) are accumulated in many extracellular matrixes such as ligament fibers, and it can functions as cellular signal through its receptor (RAGE), contributing to various events such as atherosclerosis or oxidative stress. However, its role in OPLL formation is not yet known. Therefore, we performed high-through-put RNA sequencing on primary posterior longitudinal ligament cells treated with different doses of AGEs (1µM, 5µM and negative control), with or without BMP2 (1µM).
2016-02-16 | GSE65952 | GEO
Project description:Here we studied the glycation of bovine milk proteins by lactose as dominant sugar in milk and hexoses using tandem mass spectrometry (CID and ETD mode). In a bottom-up proteomics approach after enriching glycated peptides by boronate affinity chromatography, first we could identify 260 lactosylated peptides corresponding to 124 lactosylation sites in 28 bovine milk proteins in raw milk, raw colostrum, three brands of pasteurized milk, three brands of UHT milk, and five brands of infant formula. The same regular and additionally two lactose-free milk products (pasteurized and UHT milk) where lactose is enzymatically cleaved into the more reactive hexoses were analyzed in terms of hexosylation sites that resulted in identification of 124 hexosylated tryptic peptides corresponding to 86 glycation sites in 17 bovine milk proteins. In quantitative terms glycation increased from raw milk to pasteurized milk to UHT milk and infant formula, i.e., with the harsher processing conditions. Lactose-free milk contained significantly higher hexosylation degrees than the corresponding regular milk product.
2016-01-11 | PXD003054 | Pride
Project description:Alpha-synuclein (aSyn) is a central player in the pathogenesis of synucleinopathies due to its accumulation in typical protein aggregates in the brain. However, it is still unclear how it contributes to neurodegeneration. Type-2 diabetes mellitus is a risk factor for Parkinson’s disease (PD) and, interestingly, a common molecular alteration among these disorders is the age-associated increase in protein glycation. We hypothesized that glycation-induced neuronal dysfunction might be a contributing factor in synucleinopathies. Here, we dissected the specific impact of methylglyoxal (MGO, a glycating agent) in mice overexpressing aSyn in the brain. We found that MGO-glycation potentiates motor, cognitive, olfactory, and colonic dysfunction in aSyn transgenic (Thy1-aSyn) mice that received a single dose of MGO via intracerebroventricular (ICV) injection. aSyn accumulates in the midbrain, striatum, and prefrontal cortex, and protein glycation is increased in the cerebellum and midbrain. SWATH mass spectrometry analysis, used to quantify changes in the brain proteome, revealed that MGO mainly increase glutamatergic-associated proteins in the midbrain (NMDA, AMPA, glutaminase, VGLUT and EAAT1), but not in the prefrontal cortex, where it mainly affects the electron transport chain. Notably, the glycated proteins in the midbrain of Thy1-aSyn mice that received MGO strongly correlate with PD and dopaminergic pathways. Overall, we demonstrated that MGO-induced glycation accelerates PD-like sensorimotor and cognitive alterations and suggest that the increase of glutamatergic signaling may underly these events. Our study sheds new light into the enhanced vulnerability of the midbrain in PD-related synaptic dysfunction and suggests that glycation suppressors and anti-glutamatergic drugs may hold promise as disease-modifying therapies for synucleinopathies.
2022-05-20 | PXD032832 | Pride