|H3 histone, family 3A (H3.3A)|
|Locus||Chr. 1 q41|
|H3 histone, family 3B (H3.3B)|
|Locus||Chr. 17 q25|
Histone H3 is one of the five main histone proteins involved in the structure of chromatin in eukaryotic cells. Featuring a main globular domain and a long N-terminal tail, H3 is involved with the structure of the nucleosomes of the 'beads on a string' structure. Histone proteins are highly post-translationally modified however Histone H3 is the most extensively modified of the five histones. The term "Histone H3" alone is purposely ambiguous in that it does not distinguish between sequence variants or modification state. Histone H3 is an important protein in the emerging field of epigenetics, where its sequence variants and variable modification states are thought to play a role in the dynamic and long term regulation of genes.
Epigenetics and post-translational modifications
The N-terminal tail of histone H3 protrudes from the globular nucleosome core and can undergo several different types of post-translational modification that influence cellular processes. These modifications include the covalent attachment of methyl or acetyl groups to lysine and arginine amino acids and the phosphorylation of serine or threonine. Di- and Tri-methylation of Lysine 9 are associated with repression and heterochromatin, while mono-methylation of K4 (K4 corresponds to lysine residue at 4th position) is associated with active genes. Acetylation of histone H3 occurs at several different lysine positions in the histone tail and is performed by a family of enzymes known as histone acetyltransferases (HATs). Acetylation of lysine14 is commonly seen in genes that are being actively transcribed into RNA.
Mammalian cells have seven known sequence variants of histone H3. These are denoted as Histone H3.1, Histone H3.2, Histone H3.3, Histone H3.4 (H3T), Histone H3.5, Histone H3.X and Histone H3.Y but have highly conserved sequences differing only by a few amino acids. Histone H3.3 has been found to play an important role in maintaining genome integrity during mammalian development. Histone variants from different organisms, their classification and variant specific features can be found in "HistoneDB - with Variants" database.
Histone H3s are coded by several genes in the human genome, including:
- H3.1: HIST1H3A, HIST1H3B, HIST1H3C, HIST1H3D, HIST1H3E, HIST1H3F, HIST1H3G, HIST1H3H, HIST1H3I, HIST1H3J
- H3.2: HIST2H3A, HIST2H3C, HIST2H3D
- H3.3: H3F3A, H3F3B
Epigenetic modifications of histone tails in specific regions of the brain are of central importance in addictions, and much of the work on addiction has focused on histone H3 epigenetic post-translational modifications. Once particular epigenetic alterations occur, they appear to be long lasting "molecular scars" that may account for the persistence of addictions.
Cigarette smokers (about 21% of the US population) are usually addicted to nicotine. After 7 days of nicotine treatment of mice, acetylation of both histone H3 and histone H4 was increased at the FosB promoter in the nucleus accumbens of the brain, causing 61% increase in FosB expression. This would also increase expression of the splice variant Delta FosB. In the nucleus accumbens of the brain, Delta FosB functions as a "sustained molecular switch" and "master control protein" in the development of an addiction.
About 7% of the US population is addicted to alcohol. In rats exposed to alcohol for up to 5 days, there was an increase in histone 3 lysine 9 acetylation in the pronociceptin promoter in the brain amygdala complex. This acetylation is an activating mark for pronociceptin. The nociceptin/nociceptin opioid receptor system is involved in the reinforcing or conditioning effects of alcohol.
Cocaine addiction occurs in about 0.5% of the US population. Repeated cocaine administration in mice induces hyperacetylation of Histone H3 or Histone H4 at 1,696 genes in one brain "reward" region [the nucleus accumbens] and deacetylation at 206 genes. At least 45 genes, shown in previous studies to be upregulated in the nucleus accumbens of mice after chronic cocaine exposure, were found to be associated with hyperacetylation of H3 or H4. Many of these individual genes are directly related to aspects of addiction associated with cocaine exposure. 
Walker et al. in 2015 tabulated a large number histone H3 acetylations and methylations occurring in various regions of the brain due to drug or alcohol abuse and affecting expression of genes with roles in addiction.
In rodent models, many agents causing addiction, including nicotine, alcohol, cocaine, heroin and methampheamine, cause DNA damage in the brain. During repair of DNA damages some individual repair events may alter the acetylations or methylations of histones at the sites of damage, or cause other epigenetic alterations, and thus leave an epigenetic scar on chromatin. Such epigenetic scars likely contribute to the persistent epigenetic changes found in addictions.
In 2013, 22.7 million persons aged 12 or older needed treatment for an illicit drug or alcohol use problem (8.6 percent of persons aged 12 or older).
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