Non-enzymatic covalent modifications: a new link between metabolism and epigenetics

Qingfei Zheng,Akhil Upad,Igor Maksimovic,Yael David

doi:10.1007/s13238-020-00722-w

Abstract

Epigenetic modifications, including those on DNA and histones, have been shown to regulate cellular metabolism by controlling expression of enzymes involved in the corresponding metabolic pathways. In turn, metabolic flux influences epigenetic regulation by affecting the biosynthetic balance of enzyme cofactors or donors for certain chromatin modifications. Recently, non-enzymatic covalent modifications (NECMs) by chemically reactive metabolites have been reported to manipulate chromatin architecture and gene transcription through multiple mechanisms. Here, we summarize these recent advances in the identification and characterization of NECMs on nucleic acids, histones, and transcription factors, providing an additional mechanistic link between metabolism and epigenetics.

Highlights

The genetic information of eukaryotes and archaea is packaged in the nucleus as a dynamic nucleoprotein chromatin complex that stores it efficiently and allows it to remain readily accessible (Ammar et al, 2012)
We summarize recent advances in nonenzymatic covalent modification (NECM) characterization, categorize them based on chemical reactions, and discuss their corresponding functions in disease progression, subsequently providing new perspectives regarding the link between metabolism, diet, and epigenetic regulation
While NECMs are long-established in biochemistry, emergent questions surrounding aberrant metabolism-related human diseases have revitalized renewed interest in them

Summary

INTRODUCTION

The genetic information of eukaryotes and archaea is packaged in the nucleus as a dynamic nucleoprotein chromatin complex that stores it efficiently and allows it to remain readily accessible (Ammar et al, 2012). The epigenetic impacts of histone glycation were shown to be dependent on sugar concentration and exposure time These results were summarized in a two-stage histone MGO-glycation damage model, which proposed that the initial acute exposure stage introduces a low number of scattered adducts induces chromatin 'relaxation', transitions to fiber compaction following chronic exposure due to AGE and cross-link formation (Fig. 3B) (Zheng et al, 2019). MGO selectively modifies KEAP1 to form a methylimidazole crosslink between proximal cysteine and arginine residues, resulting in the covalent dimerization of KEAP1 as well as the accumulation of NRF2 once more (Fig. 3C) (Bollong et al, 2018) These findings illustrate that sugar molecules can influence epigenetic events through glycation of transcription factors and/or their associated regulatory proteins. Since excessive glycation forms crosslinks within chromatin, which blocks transcription, distinct pathways have evolved to

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CONCLUSIONS AND PERSPECTIVES

COMPLIANCE WITH ETHICS GUIDELINES