Reversible Histone Glycation Drives Disease-Associated Changes in Chromatin Architecture
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE121252 | GEO | 2019/02/14
REPOSITORIES: GEO
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Project description:Reversible Histone Glycation Drives Disease-Associated Changes in Chromatin Architecture
| PRJNA496485 | ENA
Project description:Cancer cells undergo profound metabolic reprogramming that elevates the intracellular levels of reactive byproducts such as methylglyoxal (MGO), which can non-enzymatically modify macromolecules in a process known as glycation. Histones are particularly susceptible to glycation, resulting in substantial alterations to chromatin structure and the epigenetic landscape. However, the mechanism by which histone glycation alters epigenetic landscape and impacts specific transcriptional output in vivo has remained unclear due to the lack of high-resolution tools. Here, we utilize adduct-, site-, and target-specific antibodies we developed against histone H3 glycation at arginine 17 (H3R17MG-H1), one of the most abundant histone glycation marks, to perform precise detection and enrichment of this mark. With these, we show that H3 glycation preferentially accumulates in euchromatin and directly crosstalks with a key active transcription-associated mark, H3K4me3, at transcription start sites. Mechanistically, H3 glycation antagonizes global H3K4me3 through dual pathways: by preventing the recruitment of WDR5-containing methyltransferase complexes to glycated H3 and by transcriptionally inducing KDM5 demethylases expression. The combined effects lead to genome-wide depletion of H3K4me3 and reprogramming of cellular transcriptional networks. Our findings reveal a distinct role for histone glycation as a potent modulator of epigenetic landscape and transcriptional output, serving as a direct link between altered metabolism and cell fate.
2026-03-07 | GSE317232 | GEO
Project description:Cancer cells undergo profound metabolic reprogramming that elevates the intracellular levels of reactive byproducts such as methylglyoxal (MGO), which can non-enzymatically modify macromolecules in a process known as glycation. Histones are particularly susceptible to glycation, resulting in substantial alterations to chromatin structure and the epigenetic landscape. However, the mechanism by which histone glycation alters epigenetic landscape and impacts specific transcriptional output in vivo has remained unclear due to the lack of high-resolution tools. Here, we utilize adduct-, site-, and target-specific antibodies we developed against histone H3 glycation at arginine 17 (H3R17MG-H1), one of the most abundant histone glycation marks, to perform precise detection and enrichment of this mark. With these, we show that H3 glycation preferentially accumulates in euchromatin and directly crosstalks with a key active transcription-associated mark, H3K4me3, at transcription start sites. Mechanistically, H3 glycation antagonizes global H3K4me3 through dual pathways: by preventing the recruitment of WDR5-containing methyltransferase complexes to glycated H3 and by transcriptionally inducing KDM5 demethylases expression. The combined effects lead to genome-wide depletion of H3K4me3 and reprogramming of cellular transcriptional networks. Our findings reveal a distinct role for histone glycation as a potent modulator of epigenetic landscape and transcriptional output, serving as a direct link between altered metabolism and cell fate.
2026-03-07 | GSE317229 | GEO
Project description:Cancer cells undergo profound metabolic reprogramming that elevates the intracellular levels of reactive byproducts. These include methylglyoxal (MGO), which can non-enzymatically modify macromolecules in a process known as glycation. Histones are particularly susceptible to glycation, resulting in substantial alterations to chromatin structure and the epigenetic landscape. However, the mechanism by which this impacts specific transcriptional outputs has been difficult to interrogate due to the lack of high-resolution tools. Here, we utilize adduct-, site-, and target-specific antibodies we developed against glycated histone H3 arginine 17 (H3R17MG-H1), one of the most abundant histone glycation marks, to determine its chromatin localization. We show that H3R17MG-H1 preferentially accumulates in euchromatin and directly crosstalks with H3K4me3, a key positive mark of activity at transcription start sites. Mechanistically, H3R17MG-H1 antagonizes global H3K4me3 through dual pathways: by preventing the local recruitment of WDR5-containing methyltransferases and by transcriptionally inducing KDM5 demethylases. The combined effects lead to a genome-wide depletion of H3K4me3 and reprogramming of cellular transcriptional networks. Overall, our findings reveal a distinct role for histone glycation as a potent modulator of the epigenetic landscape and transcriptional outputs, serving as a direct link between altered metabolism and epigenetic state.
2026-03-07 | GSE318078 | GEO
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:Glycation of apolipoprotein A-I (apoA-I) compromises its cardiovascular protection, yet its pathogenic landscape remains poorly defined. Using unbiased glycation proteomics, we profiled apoA-I glycation in HDL from 1,154 patients with type 2 diabetes mellitus with or without coronary atherosclerosis (CAS). CAS-associated glycation types, frequencies, and key sites enabled construction of an apoA-I glycation index. An engineered anti-glycation apoA-I mutant restored HDL reverse cholesterol transport and inhibited atherogenesis by preventing TR4-mediated suppression of macrophage cholesterol efflux.
2026-01-22 | PXD073437 |
Project description:Non-enzymatic reactions in glycolysis lead to the accumulation of methylglyoxal (MGO), a reactive precursor to advanced glycation end-products (AGEs), which has been hypothesized to drive obesity and aging-associated pathologies. A combination of nicotinamide, lipoic acid, thiamine, pyridoxamine, and piperine (Gly-Low), was identified to lower glycation by reducing MGO and MGO-derived AGE, MG-H1, in mice. Administration of Gly-Low reduced food consumption, lowered body weight, improved insulin sensitivity, and increased survival in both leptin receptor-deficient (Leprdb) and wild-type C57B6/J mice. Unlike caloric restriction, Gly-Low modulated hypothalamic signaling by upregulating mTOR pathway signaling to inhibit ghrelin-mediated hunger response. Gly-Low also slowed hypothalamic aging and increased survival when administered as a late-life intervention, suggesting its potential benefits in ameliorating age-associated decline by inducing voluntary caloric restriction and reducing glycation.
2025-02-28 | GSE234483 | GEO
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