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Dual mechanisms for the antagonistic crosstalk between H3 glycation and H3K4me3

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE318078 | GEO | 2026/03/07

REPOSITORIES: GEO

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Dual mechanisms for the antagonistic crosstalk between H3 glycation and H3K4me3 [CUT&Tag]

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.

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Dual mechanisms for the antagonistic crosstalk between H3 glycation and H3K4me3 [RNA-Seq]

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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.

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