Cells are continuously subjected to an array of reactive chemical species which are produced both endogenously through metabolic pathways and taken up exogenously by diet and exposure to drugs or toxins. As a result, proteins often undergo non-enzymatic covalent modifications (NECMs) by these chemically reactive/toxic species, which can alter protein structure, function, stability and binding partner affinity. NECMs accumulate over time and are linked to various diseases such as Alzheimer’s disease, cancer and diabetes. In the cellular proteome, histones have some of the longest half-lives, making them prime targets for NECMs. In addition, histones have emerged as key regulators of transcription, a function that is primarily controlled by modification to their tails. These modifications are usually installed or removed enzymatically, but recent evidence suggests that some may also occur non-enzymatically. We found that the non-enzymatic reaction between sugars and amines (termed glycation), which is the hallmark of diabetes, specifically accumulates on histones. This pathophysiological modification has global ramifications on histone enzymatic modifications, the assembly and stability of nucleosomes, and the three-dimensional topology of chromatin. Importantly, we identified a physiologic regulation mechanism for restraining this damage in the form of DJ-1, which functions as a potent histone deglycase (Zheng Q. et al, <i>Nature Communications</i>, In press). Collectively, our results suggest a new mechanism for cellular metabolic damage through epigenetic perturbation, with far-reaching implications in pathogenesis and potential future therapeutics.

Reversible histone glycation drives disease-associated changes in chromatin architecture

2019 Fall National Meeting

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