Histone H3

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H3 histone, family 3A (H3.3A)
Identifiers
SymbolH3F3A
Alt. symbolsH3F3
Entrez3020
HUGO4764
OMIM601128
RefSeqNM_002107
UniProtQ66I33
Other data
LocusChr. 1 q41
H3 histone, family 3B (H3.3B)
Identifiers
SymbolH3F3B
Entrez3021
HUGO4765
OMIM601058
RefSeqNM_005324
UniProtP84243
Other data
LocusChr. 17 q25

Histone H3 is one of the five main histone proteins involved in the structure of chromatin in eukaryotic cells.[1][2] 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.[3][4] 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.

Sequence variants

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.[5][6] Histone H3.3 has been found to play an important role in maintaining genome integrity during mammalian development.[7] Histone variants from different organisms, their classification and variant specific features can be found in "HistoneDB - with Variants" database.

Genetics

Histone H3s are coded by several genes in the human genome, including:

Addiction

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.[8][9] Once particular epigenetic alterations occur, they appear to be long lasting "molecular scars" that may account for the persistence of addictions.[10][11]

Cigarette smokers (about 21% of the US population[12]) are usually addicted to nicotine.[13] 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.[14] 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.[15][16]

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.[17]

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.[18][19] 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.[19][20]

Walker et al.[21] 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,[22][23] alcohol,[24] cocaine,[25] heroin[26] and methampheamine,[27][28] 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.[11][10] 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).[12]

See also

H1 H2A H2B H4

References

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  2. Hartl Daniel L.; Freifelder David; Snyder Leon A. (1988). Basic Genetics. Boston: Jones and Bartlett Publishers. ISBN 0-86720-090-1.
  3. Rosenfeld JA, Wang Z, Schones DE, Zhao K, DeSalle R, Zhang MQ (March 2009). "Determination of enriched histone modifications in non-genic portions of the human genome". BMC Genomics. 10: 143. doi:10.1186/1471-2164-10-143. PMC 2667539. PMID 19335899.
  4. Lachner M, O'Carroll D, Rea S, Mechtler K, Jenuwein T (Mar 2001). "Methylation of histone H3 lysine 9 creates a binding site for HP1 proteins". Nature. 410 (6824): 116–20. doi:10.1038/35065132. PMID 11242053.
  5. Marzluff WF, Gongidi P, Woods KR, Jin J, Maltais LJ (Nov 2002). "The human and mouse replication-dependent histone genes". Genomics. 80 (5): 487–98. doi:10.1016/S0888-7543(02)96850-3. PMID 12408966.
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  7. Jang CW, Shibata Y, Starmer J, Yee D, Magnuson T (Jul 2015). "Histone H3.3 maintains genome integrity during mammalian development". Genes & Development. 29 (13): 1377–92. doi:10.1101/gad.264150.115. PMC 4511213. PMID 26159997.
  8. Hitchcock LN, Lattal KM (2014). "Histone-mediated epigenetics in addiction". Prog Mol Biol Transl Sci. 128: 51–87. doi:10.1016/B978-0-12-800977-2.00003-6. PMC 5914502. PMID 25410541.
  9. Cadet JL (January 2016). "Epigenetics of Stress, Addiction, and Resilience: Therapeutic Implications". Mol. Neurobiol. 53 (1): 545–560. doi:10.1007/s12035-014-9040-y. PMC 4703633. PMID 25502297.
  10. 10.0 10.1 Robison AJ, Nestler EJ (October 2011). "Transcriptional and epigenetic mechanisms of addiction". Nat. Rev. Neurosci. 12 (11): 623–37. doi:10.1038/nrn3111. PMC 3272277. PMID 21989194.
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