Chemical biology of protein arginine modifications in epigenetic regulation.

Abstract

Post-translational modifications (PTMs) of histone proteins are a hallmark of epigenetic regulation. They provide a mechanism to modulate chromatin structure and constitute the main features of the so-called “histone code”.1 The proposed function of this code is to integrate exogenous and endogenous signals into a diverse set of histone PTM patterns to enable the epigenetic control of gene expression. The key regulators of this process are the so-called “writers” and “erasers”, which act by dynamically modifying histones, and other chromatin-associated proteins, as well as the “readers”, which interpret these PTMs, thereby facilitating the downstream activation or repression of gene expression.2 The writers are histone-modifying enzymes that can be grouped according to their amino acid substrate preference, affecting mainly lysine, arginine, and serine residues.3 These enzymes can be further classified according to the type of covalent modification that they catalyze. Histone modifications include acetylation, methylation, phosphorylation, and the more recently described modifications of citrullination, ubiquitination, SUMOylation, proline isomerization, O-GlcNAcylation, and ADP-ribosylation.1b,3 On the basis of detailed mass spectrometric analyses, there are at least 15 different types of covalent histone modifications,4 and since histone proteins are modified at multiple sites, and different stoichiometries, the total number of histone marks is >160.5 Although our understanding of how histone modifications contribute to the epigenetic control of gene transcription has grown immensely over the past ∼15 years, the precise impact of this vast number of modifications, not to mention the crosstalk between them, has yet to be fully realized. Histone proteins are small, highly basic proteins consisting of a globular domain and flexible N-terminal and C-terminal tails that protrude from the nucleosome. The core histone proteins (histones H2A, H2B, H3, and H4) form an octameric particle consisting of two H2A–H2B dimers and an H3–H4 tetramer, around which wrap two helical turns of DNA (∼150 bp).6 This structure, which is generally termed a nucleosome, comprises the basic building block of higher order chromatin structures that are further organized through the function of linker histones such as histone H1. On the basis of nucleosome positioning studies, around 80% of the yeast genome and even 99% of the mappable genome of human granulocytes is occupied by nucleosomes, thereby highlighting the importance of nucleosome-packaged DNA for eukaryotic cells.7 Importantly, while histone PTMs are found throughout the entire protein, they are most often clustered within the N-terminal tail. Although research on histone lysine modifications has drawn considerable attention and even resulted in the approval of novel anticancer drugs,8 the modification of histone arginine residues is a recently emerging nucleosomal mark of similar importance (Figure ​(Figure11). Figure 1 N-terminal tails of histone proteins are the preferred targets of histone-modifying enzymes. The major modifications of histone arginine residues are citrullination and methylation. Abbreviations: Cit, citrulline; MMA, monomethylarginine; ADMA, asymmetric ...