Histone H4

H4 histone, family 3
Identifiers
Symbol H4F3
Entrez 3023
HUGO 4780
UniProt P62805
Other data
Locus Chr. 3 q13.13

Histone H4 H4 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, H4 is involved with the structure of the nucleosome of the 'beads on a string' organization. Histone proteins are highly post-translationally modified. Covalently bonded modifications include acetylation and methylation of the N-terminal tails. These modifications may alter expression of genes located on DNA associated with its parent histone octamer.[1][2] Histone H4 is an important protein in the structure and function of chromatin, where its sequence variants and variable modification states are thought to play a role in the dynamic and long term regulation of genes.

Genetics

Histone H4 is encoded in multiple genes at different loci including: HIST1H4A, HIST1H4B, HIST1H4C, HIST1H4D, HIST1H4E, HIST1H4F, HIST1H4H, HIST1H4I, HIST1H4J, HIST1H4K, HIST1H4L, HIST2H4A, HIST2H4B, HIST4H4, Hip

Evolution

Histone proteins are among the most highly conserved eukaryotic proteins. For example, the amino acid sequence of histone H4 from a pea and cow differ at only 2 out of the 102 positions. This evolutionary conservation suggests that the functions of histone proteins involve nearly all of their amino acids so that any change is deleterious to the cell. Most changes in histone sequences are lethal; the few that are not lethal cause changes in the pattern of gene expression as well as other abnormalities.[3]

Structure

Histone H4 is a 102 to 135 amino acid protein which shares a structural motif, known as the histone fold, formed from three a-helices connected by two loops. Histone proteins H3 and H4 bind to form a H3-H4 dimer, two of these H3-H4 dimers combine to form a tetramer. This tetramer further combines with two H2a-H2b dimers to form the compact Histone octamer core.[3]

Sequence Variants

Histone H4 is one of the slowest evolving proteins, and there appear to be no known sequence variants of histone H4. However, there are H4 genes that are constitutively expressed throughout the cell cycle that encode for proteins that are identical in sequence to the major H4.[4] The reason for a lack of sequence variants remains unclear.

Post-Translational Modifications

Eukaryotic organisms can produce small amounts of specialized variant core histones that differ in amino acid sequence from the main ones. These variants with a variety of covalent modifications on the N-terminal can be added to histones making possible different chromatin structures that are required for DNA function in higher eukaryotes. Potential modifications include methylation (mono-, di-, or tri-methylation) or acetylation on the tails.[3]

Methylation

Histone methylation occurs on arginine, lysine and histidine amino acids residues. Mono-, di- or tri-methylation has been discovered on histone H2A, H3 and H4.[5] Histone methylation has been associated with various cellular functions such as transcription, DNA replication, and DNA damage response including repair, heterochromatin formation, and somatic cell reprogramming. Among these biological functions, transcriptional repression and activation are the most studied.[5] Studies have shown that H4R3 methylation by PRMT1 (a histone methyltransferase) appears to be essential in vivo for the establishment or maintenance of a wide range of “active” chromatin modifications. Also methylation of histone H4 by PRMT1 was sufficient to permit subsequent acetylation on the N-terminal tail. However, acetylation of H4 inhibits its methylation by PRMT1.[6]

Acetylation

Acetylation of histones is thought to relax condensed heterochromatin as the negative charge of acetyl groups can repel the DNA phosphate backbone charges, thus reducing the histone binding affinity for DNA. This hypothesis was validated by the discovery of the histone acetyltransferase (HAT) activity of several transcriptional activator complexes.[5] Histone acetylation influences chromatin structure in several ways. First, it can provide a tag for the binding of proteins that contain areas which recognize the acetylated tails. Secondly, it can block the function of chromatin remodelers.[7] Thirdly, it neutralizes the positive charge on lysines.[7] Acetylation of histone H4 on lysine 16 (H4K16Ac) is especially important for chromatin structure and function in a variety of eukaryotes and is catalyzed by specific histone lysine acetyltransferases (HATs). H4K16 is particularly interesting because this is the only acetylatable site of the H4 N-terminal tail, and can influence the formation of a compact higher-order chromatin structure.[7] H4K16Ac also has roles in transcriptional activation and the maintenance of euchromatin.[8]

References

  1. ↑ Bhasin M, Reinherz EL, Reche PA (2006). "Recognition and classification of histones using support vector machine". J. Comput. Biol. 13 (1): 102–12. doi:10.1089/cmb.2006.13.102. PMID 16472024.
  2. ↑ Hartl Daniel L.; Freifelder David; Snyder Leon A. (1988). Basic Genetics. Boston: Jones and Bartlett Publishers. ISBN 0-86720-090-1.
  3. 1 2 3 Alberts B, Johnson A, Lewis J, Raff M, Roberts K, Walter P (2008). Molecular biology of the cell.
  4. ↑ Kamakaka, Biggins (2005). "Histone variants: deviants?". Genes and Dev. 19: 295–316. doi:10.1101/gad.1272805.
  5. 1 2 3 Kim JK, Samaranayake M, Pradhan S (2009). "Epigenetic mechanisms in mammals". Cellular and Molecular Life Sciences. 66 (4): 596–612. doi:10.1007/s00018-008-8432-4.
  6. ↑ Huang, Litt, and Felsenfeld (2005). Methylation of histone H4 by arginine methyltransferase PRMT1 is essential in vivo for many subsequent histone modifications (2005), National Institutes of Health
  7. 1 2 3 Tylor GC, Eskeland R, Hekimoglu-Balkan B, Pradeepa MM, Bickmore WA. "H4K16 acetylation marks active genes and enhancers of embryonic stem cells, but does not alter chromatin compaction.". Genome Res. 23: 2053–2065.
  8. ↑ Shrogren-Knaak et al. Histone H4-K16 Acetylation Controls Chromatin Structure and Protein Interactions (2006)

See also

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