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

Nat Commun. 2019 Mar 20;10(1):1289. doi: 10.1038/s41467-019-09192-z.

Qingfei Zheng ¹, Nathaniel D Omans ¹ ², Rachel Leicher ³ ⁴, Adewola Osunsade ¹ ⁴, Albert S Agustinus ¹, Efrat Finkin-Groner ¹, Hannah D'Ambrosio ¹, Bo Liu ⁵, Sarat Chandarlapaty ⁵, Shixin Liu ³, Yael David ⁶ ⁷ ⁸ ⁹

Affiliations

1 Chemical Biology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, 10065, USA.
2 Tri-Institutional Training Program in Computational Biology and Medicine, New York, NY, 10065, USA.
3 Laboratory of Nanoscale Biophysics and Biochemistry, Rockefeller University, New York, NY, 10065, USA.
4 Tri-institutional PhD Program in Chemical Biology, New York, NY, 10065, USA.
5 Human Oncology & Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
6 Chemical Biology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, 10065, USA. davidshy@mskcc.org.
7 Tri-institutional PhD Program in Chemical Biology, New York, NY, 10065, USA. davidshy@mskcc.org.
8 Department of Pharmacology, Weill Cornell Medical College, New York, NY, 10065, USA. davidshy@mskcc.org.
9 Department of Physiology, Biophysics and Systems Biology, Weill Cornell Medical College, New York, NY, 10065, USA. davidshy@mskcc.org.

PMID: 30894531 DOI: 10.1038/s41467-019-09192-z

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.

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