There are 5 histone families (H1-H5) split into two broad groups: core histones (H2A, H2B, H3, and H4) and linker histones (H1 and H5). Histones undergo a large number of post-translational modifications (PTMs), including acetylation, lysine and arginine methylation, citrullination, phosphorylation, and ubiquitination. These modifications function to regulate both nucleosome structure and stability, and the recruitment of chromatin binding proteins. Here we will focus on H2A, H2B, and H4 histone proteins and their PTMs. Different types of enzymes, termed writers, readers and erasers, interact with histones to affect chromatin structure and transcription. Writers are enzymes that add PTMs, while erasers are enzymes that remove PTMs. Reader proteins bind to the PTMs and function to regulate changes in chromatin structure and gene expression. This pathway discusses the writers and erasers for histones H2A, H2B and histone H4, as well as the amino acid residues they modify.
- Histone acetyltransferases (HATs) are writers that acetylate lysine residues, including histone H2A Lys5, H2B Lys5, 12, 15, 20, and H4 Lys5, 8, 12, 16. Conversely, the deacytelation of these residues is performed by erasers known as histone deacetylases (HDACs). Acetylation of lysine residues neutralizes the positive charge on histones, allowing DNA-binding proteins better access to the DNA and resulting in activation of gene expression. In addition, acetylation creates binding sites for reader proteins containing bromodomains and YEATs domains.
- Histone lysine methyltransferases (KMTs) are writers that add methyl groups to lysine residues, which may be removed by erasers known as histone lysine demethylases (KDMs). For example, histone H4 Lys20 can be mono-, di-, or tri-methylated, and each methylation state serves a distinct function. Unlike acetylation, methylation does not affect histone charge; instead, it regulates recognition by and interaction with chromatin-binding proteins that are important for transcription. Additionally, arginine residues, including H2A Arg 3, H2B Arg11, and H4 Arg3 can be mono- or di-methylated (symmetric and asymmetric) by writer proteins known as protein arginine methyltransferases (PRMTs), leading to either gene activation or repression. Methyl-arginine residues can be converted to citrulline by protein-arginine deaminase (PADI) proteins. Methylation of lysine and arginine residues creates binding sites for reader proteins containing chromodomains, MBT domains, Tudor domains, WD40 domains and PHD fingers.
- Multiple kinases and phosphatases can phosphorylate and dephosphorylate serine, threonine, and tyrosine residues on histone proteins, respectively. Phosphorylated residues tend to be concentrated at the N-terminus of histone tails, and like acetylation, reduce the positive charge of the histones. In addition, phosphorylated residues can generate binding sites for reader proteins containing 14-3-3 domains, or function to mask binding sites for other reader proteins. Moreover, phosphorylated histone residues are highly associated with chromosome condensation during mitosis and meiosis.
- Lastly, histone ubiquitination occurs when small, 76-amino acid ubiquitin molecules are attached to lysine residues by 3 specialized enzymes known as the E1-activating, E2-conjugating, and E3-ligase enzymes. Ubiquitination marks can either activate or repress transcription. For example, two prominent sites of ubiquitination are H2A Lys119 and H2B Lys120. H2A mono-ubiquitination at the Lys119 residue by the polycomb repressor complex PRC1 leads to gene silencing, while ubiquitination of H2B at the Lys120 residue by the RNF20/40 complex leads to transcriptional activation.