(De)Toxifying the Epigenetic Code

Abstract

Cells are continuously subjected to an array of reactive/toxic 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 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 of their tails. These modifications are usually installed or removed enzymatically, but recent evidence suggests that some may also occur non-enzymatically. Despite the vast knowledge detailing the relationship between histone modifications and gene regulation, NECMs on histones remain poorly explored. A major reason for this difference stems from the fact that, unlike their enzymatically installed counterparts, NECMs are difficult to both control and test in vivo. Here, we review advances in our understanding of the effect non-enzymatic covalent modifications (NECMs) have on the epigenetic landscape, cellular fate, and their implications in disease. Cumulatively, this illustrates how the epigenetic code is directly toxified by chemicals and detoxified by corresponding eraser enzymes.

Non-enzymatic Lysine Lactoylation of Glycolytic Enzymes

“…Lys acetylation, like many PTMs, is regulated enzymatically through the addition (Lys acetyltransferases) and removal (Lys deacetylases) of the acetyl group (Zhao et al, 2010). While most PTMs are tightly regulated, there is growing interest in non-enzymatic PTMs and their role in metabolic regulation and cell homeostasis (Moellering and Cravatt, 2013;Zheng et al, 2019b).…”

Protein arginine deiminase 4 antagonizes methylglyoxal-induced histone glycation

“…Whereas the most well-characterized histone modifications are enzymatic, in the past few years it has become clear that histones are also prime substrates of nonenzymatic covalent modifications that induce changes in chromatin structure and function 17 . We recently found that core histones are subjected to MGO glycation and that these adducts change chromatin architecture, the epigenetic landscape, and transcription, and particularly accumulate in disease states 18,19 .…”

Non-enzymatic Covalent Modifications as a New Chapter in the Histone Code

“…Several protein systems have previously been described as being capable of intercepting reactive metabolites and byproducts both in the cytosol and in the nucleus before they can reach the histones (Figure 3A). In addition to the glyoxalase cycle mentioned earlier, aldehyde and lactate dehydrogenases utilize NAD + as a cofactor and directly oxidize aldehyde and lactate molecules into their respective less deleterious carboxylates [51,52]. Conversely, aldo-keto reductases use NADPH as a cofactor to reduce aldehydes into alcohols, which are more easily managed [53].…”