Histone H4 is one of the five main

histone In biology, histones are highly basic proteins abundant in lysine and arginine residues that are found in eukaryotic cell nuclei and in most Archaeal phyla. They act as spools around which DNA winds to create structural units called nucleosomes ...

protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residue (biochemistry), residues. Proteins perform a vast array of functions within organisms, including Enzyme catalysis, catalysing metab ...

s involved in the structure of

chromatin Chromatin is a complex of DNA and protein found in eukaryote, eukaryotic cells. The primary function is to package long DNA molecules into more compact, denser structures. This prevents the strands from becoming tangled and also plays important r ...

eukaryotic The eukaryotes ( ) constitute the Domain (biology), domain of Eukaryota or Eukarya, organisms whose Cell (biology), cells have a membrane-bound cell nucleus, nucleus. All animals, plants, Fungus, fungi, seaweeds, and many unicellular organisms ...

cells. Featuring a main globular domain and a long N-terminal tail, H4 is involved with the structure of the

nucleosome A nucleosome is the basic structural unit of DNA packaging in eukaryotes. The structure of a nucleosome consists of a segment of DNA wound around eight histone, histone proteins and resembles thread wrapped around a bobbin, spool. The nucleosome ...

of the 'beads on a string' organization. Histone proteins are highly post-translationally modified. Covalently bonded modifications include

acetylation : In chemistry, acetylation is an organic esterification reaction with acetic acid. It introduces an acetyl group into a chemical compound. Such compounds are termed ''acetate esters'' or simply ''acetates''. Deacetylation is the opposite react ...

and

methylation Methylation, in the chemistry, chemical sciences, is the addition of a methyl group on a substrate (chemistry), substrate, or the substitution of an atom (or group) by a methyl group. Methylation is a form of alkylation, with a methyl group replac ...

of the N-terminal tails. These modifications may alter expression of genes located on DNA associated with its parent histone octamer. 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, HIST1H4G, HIST1H4H, HIST1H4I, HIST1H4J, HIST1H4K, HIST1H4L, HIST2H4A, HIST2H4B, HIST4H4.

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.

Structure

Histone H4 is a 102 to 135 amino acid protein which shares a

structural motif In a chain-like biological molecule, such as a protein or nucleic acid, a structural motif is a common three-dimensional structure that appears in a variety of different, evolutionarily unrelated molecules. A structural motif does not have t ...

, 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 A tetramer () (''tetra-'', "four" + '' -mer'', "parts") is an oligomer formed from four monomers or subunits. The associated property is called ''tetramery''. An example from inorganic chemistry is titanium methoxide with the empirical formula ...

. This tetramer further combines with two H2a-H2b dimers to form the compact Histone octamer core.

Sequence variants

Histone H4 is one of the slowest evolving proteins. 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. Variants in human histone H4 were only recently discovered and are very rare. Pathogenic '' de novo'' missense variants have been identified in six H4 genes ( HIST1H4C, HIST1H4D, HIST1H4E, HIST1H4F, HIST1H4I, HIST1H4J) in 33 individuals total, all presenting with

neurodevelopmental The development of the nervous system, or neural development (neurodevelopment), refers to the processes that generate, shape, and reshape the nervous system of animals, from the earliest stages of embryonic development to adulthood. The field ...

features of

intellectual disability Intellectual disability (ID), also known as general learning disability (in the United Kingdom), and formerly mental retardation (in the United States), Rosa's Law, Pub. L. 111-256124 Stat. 2643(2010).Archive is a generalized neurodevelopmental ...

and motor and/or gross developmental delay, but with variable non-neurological features. Ten amino acids were affected, six of which were found recurrently. These mutations were located within either the H4 core globular domain (involved in protein-protein interaction) or C-terminal tail (involved in post-translational modification).

Alternative translation

The Osteogenic Growth Peptide (OGP) is a 14-aa peptide produced from alternative translation of histone H4 mRNA, sharing the

C-terminal The C-terminus (also known as the carboxyl-terminus, carboxy-terminus, C-terminal tail, carboxy tail, C-terminal end, or COOH-terminus) is the end of an amino acid chain (protein or polypeptide), terminated by a free carboxyl group (-COOH). When t ...

sequence ALKRQGRTLYGFGG of histone H4. Translation is initiated at the 85th amino acid of the histone H4 mRNA, resulting in a 19-aa peptide (preOGP). This is converted into OGP through the cleavage of 5 amino-terminal residues. It is found in human and rat circulation as well as regenerating bone marrow. In blood serum it is bound to α2M along with two other binding proteins that are not clearly identified. A specific receptor has not been identified, but some signaling pathways involved in its bone-regenaration function has been elucidated.

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.

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. 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. 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.

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 Histone acetyltransferases (HATs) are enzymes that acetylation, acetylate conserved lysine amino acids on histone proteins by transferring an acetyl group from acetyl-CoA to form ε-N-acetyllysine, ε-''N''-acetyllysine. DNA is wrapped around his ...

(HAT) activity of several transcriptional activator complexes. 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. Thirdly, it neutralizes the positive charge on lysines. 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. Hypoacetylation of H4K16 appears to cause delayed recruitment of

DNA repair DNA repair is a collection of processes by which a cell (biology), cell identifies and corrects damage to the DNA molecules that encode its genome. A weakened capacity for DNA repair is a risk factor for the development of cancer. DNA is cons ...

proteins to sites of DNA damage in a mouse model of the premature aging syndrome Hutchinson Gilford progeria. H4K16Ac also has roles in transcriptional activation and the maintenance of euchromatin. Additional acetylations include K31ac and K79ac.

List of H4 modifications

H4S1p H4R3me2 H4K5ac H4K8ac H4K12ac H4K16ac H4K16adp H4K20me H4K31ac H4S47o-p H4K79ac H4K91ac H4K91ub