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. 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. 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