Epigenetic regulatory proteins play a critical role in the regulation of gene expression by controlling the availability of the DNA sequence to the cellular machinery for replication, transcription, DNA repair, recombination, and chromosome segregation. Epigenetic regulation includes the post-translational modification (PTM) of amino acid residues within histone proteins by multiple classes of enzymes (termed writer and eraser proteins). Here, we focus on PTMs in Histone H3 that play a critical roles in the regulation of chromatin structure and gene expression. Histone H3 is modified by a large number of PTMs, including acetylation, methylation, and phosphorylation. These PTMs can occur at different residues on histone H3 and regulate various processes including nuclear organization, chromatin structure, and recruitment of chromatin binding proteins (termed reader proteins).
Acetylation of lysine residues is mediated by histone lysine acetyltransferases (HATs) and is removed by histone deacetylases (HDACs). Acetylated lysine residues on histone H3 include Lys4, 9, 14, 18, 23, 27, 36, and 56. Acetylation neutralizes the positive charge on histone H3, allowing DNA-binding proteins better access to the DNA and resulting in activation of gene expression. In addition, acetylated lysine residues generate binding domains for reader proteins containing bromodomains and YEATS domains.
Histone lysine methylation is mediated by lysine methyltransferases (KMTs) and is removed by lysine demethylases (KDMs). Methylated lysine residues on histone H3 include Lys4, 9, 27, 36, and 79. Each lysine residue can be mono-, di-, or tri-methylated, and each methylation state appears to serve different functions. Methylation does not affect histone charge; instead, it regulates binding of reader proteins and their associated protein complexes. For example, tri-methylation of histone H3 on Lys27 (H3K27me3) by the polycomb repressor complex 2 (PRC2) generates a binding site for the PRC1 complex, both of which function to generate compact chromatin that is repressive to transcription. Alternatively, H3K4me3 is a mark bound by multiple reader proteins that function to activate transcription. Methyl-lysine residues provide binding domains for reader proteins containing chromodomains, MBT domain, WD40 domains and PHD fingers.
Arginine residues, including Arg 2, 17, and 26, can be mono- or di-methylated (symmetrically or asymmetrically) by protein arginine methyltransferases (PRMTs), leading to either gene activation or repression. Moreover, methyl-arginine residues can be converted to citrulline by protein arginine deaminase (PADI) proteins. Methylation of arginine residues creates binding sites for reader proteins containing Tudor domains, PHD fingers and WD40 domains.
Lastly, histone H3 is phosphorylated on serine, threonine, and tyrosine residues by kinases, and can be dephosphorylated by phosphatases. Phosphorylated residues tend to be concentrated within the N-terminal tail of histone H3, and like acetylation, reduce the positive charge of the histone. 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 (i.e. HP1 chromodomain protein binding to H3K9Me3 is blocked by H3S10Phos). Phosphorylation of histone H3 Ser10, along with Thr3, Thr11, and Ser28, is mostly associated with chromosome condensation during mitosis and meiosis. In particular, phosphorylation of Ser10 is quite often used as a marker for cells in mitosis. However, Ser10 and Ser28 phosphorylation also play a minor role in transcriptional activation, particularly at immediate-early genes.
We would like to thank Dr. Jonathan Whetstine, Harvard Medical School and Massachusetts General Hospital, for reviewing this pathway.
created March 2018
