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. They act as spools around which DNA winds to create structural units called nucleosomes. Nucleosomes in turn a ...

protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, res ...

s involved in the structure of

chromatin Chromatin is a complex of DNA and protein found in 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 roles in r ...

eukaryotic Eukaryotes () are organisms whose Cell (biology), cells have a cell nucleus, nucleus. All animals, plants, fungi, and many unicellular organisms, are Eukaryotes. They belong to the group of organisms Eukaryota or Eukarya, which is one of the ...

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 Gene expression is the process by which information from a gene is used in the synthesis of a functional gene product that enables it to produce end products, protein or non-coding RNA, and ultimately affect a phenotype, as the final effect. Th ...

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 Histone H4 is a protein that in humans is encoded by the ''HIST1H4A'' gene In biology, the word gene (from , ; "...Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' o ...

, HIST1H4B,

HIST1H4C Histone H4 is a protein that in humans is encoded by the ''HIST1H4C'' gene In biology, the word gene (from , ; "...Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' o ...

HIST1H4D Histone H4 is a protein that in humans is encoded by the ''HIST1H4D'' gene In biology, the word gene (from , ; "...Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' o ...

, HIST1H4E,

HIST1H4F Histone H4 is a protein that in humans is encoded by the ''HIST1H4F'' gene In biology, the word gene (from , ; "...Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' o ...

, HIST1H4G,

HIST1H4H Histone H4 is a protein that in humans is encoded by the ''HIST1H4H'' gene In biology, the word gene (from , ; "...Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' o ...

HIST1H4I Histone H4 is a protein that, in humans, is encoded by the ''HIST1H4I'' gene In biology, the word gene (from , ; "...Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' ...

HIST1H4J Histone cluster 1, H4j is a protein that in humans is encoded by the HIST1H4J gene. Histones are basic nuclear proteins that are responsible for the nucleosome structure of the chromosomal fiber in eukaryotes. Two molecules of each of the four co ...

HIST1H4K Histone H4 is a protein that in humans is encoded by the ''HIST1H4K'' gene. Histones are basic nuclear proteins that are responsible for the nucleosome structure of the chromosomal fiber in eukaryotes. Two molecules of each of the four core histon ...

HIST1H4L Histone H4 is a protein that in humans is encoded by the ''HIST1H4L'' gene. Function Histones are basic nuclear proteins that are responsible for the nucleosome structure of the chromosomal fiber in eukaryotes. Two molecules of each of the four ...

HIST2H4A Histone H4 is a protein that in humans is encoded by the ''HIST2H4A'' gene In biology, the word gene (from , ; "...Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' o ...

, HIST2H4B,

HIST4H4 Histone H4 is a protein that in humans is encoded by the ''HIST4H4'' gene. Histones are basic nuclear proteins that are responsible for the nucleosome structure of the chromosomal fiber in eukaryote Eukaryotes () are organisms whose cells h ...

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, known as the

histone fold A histone fold is a structurally conserved Structural motif, motif found near the C-terminus in every core histone sequence in a histone octamer responsible for the binding of histones into heterodimers. The histone fold averages about 70 amino aci ...

, 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 A histone octamer is the eight-protein complex found at the center of a nucleosome core particle. It consists of two copies of each of the four core histone proteins ( H2A, H2B, H3, and H4). The octamer assembles when a tetramer, containing two ...

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 (

, HIST1H4E,

) in 33 individuals total, all presenting with neurodevelopmental features of

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

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, 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 the protein is ...

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 acetylate conserved lysine amino acids on histone proteins by transferring an acetyl group from acetyl-CoA to form ε-''N''-acetyllysine. DNA is wrapped around histones, and, by transferring ...

(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 identifies and corrects damage to the DNA molecules that encode its genome. In human cells, both normal metabolic activities and environmental factors such as radiation can cause DNA da ...

proteins to sites of DNA damage in a mouse model of the premature aging syndrome Hutchinson Gilford

progeria Progeria is a specific type of progeroid syndrome, also known as Hutchinson–Gilford syndrome. A single gene mutation is responsible for progeria. The gene, known as lamin A (LMNA), makes a protein necessary for holding the Nucleus of the cell ...

. H4K16Ac also has roles in transcriptional activation and the maintenance of

euchromatin Euchromatin (also called "open chromatin") is a lightly packed form of chromatin ( DNA, RNA, and protein) that is enriched in genes, and is often (but not always) under active transcription. Euchromatin stands in contrast to heterochromatin, whi ...

List of H4 modifications

H4S1p H4R3me H4K5ac H4K8ac H4K12ac H4K16ac H4K16adp H4K20me H4S47o-p H4K91ac H4K91ub