Histone methylation is a process by which methyl groups are transferred to amino acids of histone proteins that make up nucleosomes, which the DNA double helix wraps around to form chromosomes. Methylation of histones can either increase or decrease transcription of genes, depending on which amino acids in the histones are methylated, and how many methyl groups are attached. Methylation events that weaken chemical attractions between histone tails and DNA increase transcription because they enable the DNA to uncoil from nucleosomes so that transcription factor proteins and RNA polymerase can access the DNA. This process is critical for the regulation of gene expression that allows different cells to express different genes.
Function
Histone methylation, as a mechanism for modifying chromatin structure is associated with stimulation of neural pathways known to be important for formation of long-term memories and learning. Histone methylation is crucial for almost all phases of animal embryonic development.
Animal models have shown methylation and other epigenetic regulation mechanisms to be associated with conditions of aging, neurodegenerative diseases, and intellectual disability (Rubinstein–Taybi syndrome, X-linked intellectual disability). Misregulation of H3K4, H3K27, and H4K20 are associated with cancers. This modification alters the properties of the nucleosome and affects its interactions with other proteins, particularly in regards to gene transcription processes. Histone methylation can be associated with either transcriptional repression or activation. For example, trimethylation of histone H3 at lysine 4 (H3K4me3) is an active mark for transcription and is upregulated in hippocampus one hour after contextual fear conditioning in rats. However, dimethylation of histone H3 at lysine 9 (H3K9me2), a signal for transcriptional silencing, is increased after exposure to either the fear conditioning or a novel environment alone. Methylation of some lysine (K) and arginine (R) residues of histones results in transcriptional activation. Examples include methylation of lysine 4 of histone 3 (H3K4me1), and arginine (R) residues on H3 and H4. Addition of methyl groups to histones by histone methyltransferases, can either activate or further repress transcription, depending on the amino acid being methylated and the presence of other methyl or acetyl groups in the vicinity. Most often, for histone lysine methylations, histone methyltransferases (which methylate) are characterized as "writers", whereas demethylases are characterized as "erasers".
Mechanism
The fundamental unit of chromatin, called a nucleosome, contains DNA wound around a protein octamer. This octamer consists of two copies each of four histone proteins: H2A, H2B, H3, and H4. Each one of these proteins has a tail extension, and these tails are the targets of nucleosome modification by methylation. DNA activation or inactivation is largely dependent on the specific tail residue methylated and its degree of methylation. Histones can be methylated on lysine (K) and arginine (R) residues only, but methylation is most commonly observed on lysine residues of histone tails H3 and H4. The tail end furthest from the nucleosome core is the N-terminal (residues are numbered starting at this end). Common sites of methylation associated with gene activation include H3K4, H3K48, and H3K79. Common sites for gene inactivation include H3K9 and H3K27. Studies of these sites have found that methylation of histone tails at different residues serve as markers for the recruitment of various proteins or protein complexes that serve to regulate chromatin activation or inactivation.
Lysine and arginine residues both contain amino groups, which confer basic and hydrophobic characteristics. Lysine is able to be mono-, di-, or trimethylated with a methyl group replacing each hydrogen of its NH3+ group. With a free NH2 and NH2+ group, arginine is able to be mono- or dimethylated. This dimethylation can occur asymmetrically on the NH2 group or symmetrically with one methylation on each group. Each addition of a methyl group on each residue requires a specific set of protein enzymes with various substrates and cofactors. Generally, methylation of an arginine residue requires a complex including protein arginine methyltransferase (PRMT) while lysine requires a specific histone methyltransferase (HMT), usually containing an evolutionarily conserved SET domain.