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

Post-translational modifications (PTMs) of proteins are introduced either by the specific activity of ‘writer’ enzymes or spontaneous chemical reaction with reactive small molecules forming non-enzymatic covalent modifications (NECMs). Histones are particularly susceptible to accumulate NECMs due to their long half-lives, unstructured tails, and abundance of accessible reactive arginine and lysine residues that are key sites for regulatory enzymatic PTMs. NECMs on histones compete with enzymatic PTMs as well as alter chromatin structure, subsequently affecting tightly regulated genetic processes and ultimately resulting in global cellular phenotype changes. NECMs can be enzymatically ‘erased’ as well as prevented by scavenger systems, including both small molecules and proteins. Advances in biophysical methods, immunoassays, mass spectrometry, chemical probe development, and chemoproteomics have established a platform that can be leveraged to predict, track, manipulate, and study histone NECMs. The interior of the cell abounds with reactive species that can accumulate as non-enzymatic covalent modifications (NECMs) on biological macromolecules. These adducts interfere with many cellular processes, for example, by altering proteins’ surface topology, enzymatic activity, or interactomes. Here, we discuss dynamic NECMs on chromatin, which serves as the cellular blueprint. We first outline the chemistry of NECM formation and then focus on the recently identified effects of their accumulation on chromatin structure and transcriptional output. We next describe the known cellular regulatory mechanisms that prevent or reverse NECM formation. Finally, we discuss recently developed chemical biology platforms for probing and manipulating these NECMs in vitro and in vivo. The interior of the cell abounds with reactive species that can accumulate as non-enzymatic covalent modifications (NECMs) on biological macromolecules. These adducts interfere with many cellular processes, for example, by altering proteins’ surface topology, enzymatic activity, or interactomes. Here, we discuss dynamic NECMs on chromatin, which serves as the cellular blueprint. We first outline the chemistry of NECM formation and then focus on the recently identified effects of their accumulation on chromatin structure and transcriptional output. We next describe the known cellular regulatory mechanisms that prevent or reverse NECM formation. Finally, we discuss recently developed chemical biology platforms for probing and manipulating these NECMs in vitro and in vivo. the spontaneous adduction of a small molecule onto the lysine ε-amine or N-terminal amine via an acyl linkage. the resulting diverse group of products in a glycation chemical reaction cascade. chromatin immunoprecipitation sequencing; the process of identifying the regions where a specific mark is located in terms of genomic position. Involves the crosslinking of DNA and proteins, shearing chromatin, antibody enrichment, reverse crosslinking, digestion, and next-generation sequencing of the isolated DNA fragments. the physiologically relevant protein–DNA complex for storage and access of genetic information in eukaryotes. The fundamental unit of this complex is a nucleosome, which comprises about 150 DNA base pairs wrapped approximately 1.65 times around a histone octamer. The histone octamer itself contains two copies of each of the four core histones H2A, H2B, H3, and H4. covalent bonds linking one polymer chain to another. molecules containing two carbonyl groups. chemical species that accept electron pairs to form bonds with nucleophiles. functional groups that confer specific purification advantages. the study of phenotypic changes caused by alterations in gene expression rather than in the genetic code. the non-enzymatic modification of biological macromolecules by a reducing sugar or aldehyde-containing sugar derivative via the Maillard reaction. the metabolic pathway that describes the breakdown of glucose by enzymes into pyruvate, releasing energy in the process. the hypothesis that transcription is partly regulated by chemical modifications, primarily on unstructured histone tails. the incorporation of a lactyl moiety onto an ε-amine or N-terminal amine via an acyl linkage. the incorporation of a fatty chain as a modification on a protein. the plethora of species formed from a chemical reaction between amino acids and reducing sugars giving browned food its distinctive color and flavor. the covalent modification of proteins following their biosynthesis. the reaction of propionyl groups onto the ε-amine or N-terminal amine via an acyl linkage that can be used to remove the ability of trypsin to recognize lysine and arginine residues in mass spectrometry sample preparation. the characterization of the genetic sequences of the RNA in a sample, cell, or tissue. a cyclic chemical compound with a characteristic sulfur adjacent to a carbonyl. a modified form of cellular metabolism found in cancer cells whereby a specialized mixture of mostly anaerobic glycolysis is preferred to aerobic glycolysis.