Reversible histone glycation is associated with disease-related changes in chromatin architecture

Qingfei Zheng, Nathaniel D. Omans, Rachel Leicher, Adewola Osunsade, Albert S. Agustinus, Efrat Finkin-Groner, Hannah D’Ambrosio, Bo Liu, Sarat Chandarlapaty, Shixin Liu and Yael David ()
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Qingfei Zheng: Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center
Nathaniel D. Omans: Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center
Rachel Leicher: Rockefeller University
Adewola Osunsade: Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center
Albert S. Agustinus: Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center
Efrat Finkin-Groner: Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center
Hannah D’Ambrosio: Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center
Bo Liu: Memorial Sloan Kettering Cancer Center
Sarat Chandarlapaty: Memorial Sloan Kettering Cancer Center
Shixin Liu: Rockefeller University
Yael David: Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center

Nature Communications, 2019, vol. 10, issue 1, 1-12

Abstract: Abstract Cellular proteins continuously undergo non-enzymatic covalent modifications (NECMs) that accumulate under normal physiological conditions and are stimulated by changes in the cellular microenvironment. Glycation, the hallmark of diabetes, is a prevalent NECM associated with an array of pathologies. Histone proteins are particularly susceptible to NECMs due to their long half-lives and nucleophilic disordered tails that undergo extensive regulatory modifications; however, histone NECMs remain poorly understood. Here we perform a detailed analysis of histone glycation in vitro and in vivo and find it has global ramifications on histone enzymatic PTMs, the assembly and stability of nucleosomes, and chromatin architecture. Importantly, we identify a physiologic regulation mechanism, the enzyme DJ-1, which functions as a potent histone deglycase. Finally, we detect intense histone glycation and DJ-1 overexpression in breast cancer tumors. Collectively, our results suggest an additional mechanism for cellular metabolic damage through epigenetic perturbation, with implications in pathogenesis.

Date: 2019
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DOI: 10.1038/s41467-019-09192-z

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