Histone H4

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Structures	Swiss-model
Domains	InterPro

H4 histone, family 3
H4 histone, family 3
Identifiers
Symbol	H4F3
NCBI gene	3023
HGNC	4780
UniProt	P62805
Other data
Locus	Chr. 3 q13.13
Structures
Search for
Structures	Swiss-model
Domains	InterPro

Last updated April 01, 2024

Histone 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, 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.^[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. 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] Variants in human histone H4 were only recently discovered and are very rare.^[5]^[6]^[7]

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 features of intellectual disability 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).^[5]^[6]^[7]

Alternative translation

The Osteogenic Growth Peptide (OGP) is a 14-aa peptide produced from alternative translation of histone H4 mRNA, sharing the C-terminal 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.^[8] 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.^[9]

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.^[10] 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.^[10] 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.^[11]

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.^[10] 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.^[12] Thirdly, it neutralizes the positive charge on lysines.^[12] 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.^[12] Hypoacetylation of H4K16 appears to cause delayed recruitment of DNA repair proteins to sites of DNA damage in a mouse model of the premature aging syndrome Hutchinson Gilford progeria.^[13] H4K16Ac also has roles in transcriptional activation and the maintenance of euchromatin.^[14] Additional acetylations include K31ac and K79ac.^[15]

List of H4 modifications

Related Research Articles

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. Nucleosomes in turn are wrapped into 30-nanometer fibers that form tightly packed chromatin. Histones prevent DNA from becoming tangled and protect it from DNA damage. In addition, histones play important roles in gene regulation and DNA replication. Without histones, unwound DNA in chromosomes would be very long. For example, each human cell has about 1.8 meters of DNA if completely stretched out; however, when wound about histones, this length is reduced to about 90 micrometers (0.09 mm) of 30 nm diameter chromatin fibers.

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 proteins and resembles thread wrapped around a spool. The nucleosome is the fundamental subunit of chromatin. Each nucleosome is composed of a little less than two turns of DNA wrapped around a set of eight proteins called histones, which are known as a histone octamer. Each histone octamer is composed of two copies each of the histone proteins H2A, H2B, H3, and H4.

Histone methyltransferases (HMT) are histone-modifying enzymes, that catalyze the transfer of one, two, or three methyl groups to lysine and arginine residues of histone proteins. The attachment of methyl groups occurs predominantly at specific lysine or arginine residues on histones H3 and H4. Two major types of histone methyltranferases exist, lysine-specific and arginine-specific. In both types of histone methyltransferases, S-Adenosyl methionine (SAM) serves as a cofactor and methyl donor group.
The genomic DNA of eukaryotes associates with histones to form chromatin. The level of chromatin compaction depends heavily on histone methylation and other post-translational modifications of histones. Histone methylation is a principal epigenetic modification of chromatin that determines gene expression, genomic stability, stem cell maturation, cell lineage development, genetic imprinting, DNA methylation, and cell mitosis.

<span class="mw-page-title-main">Histone acetyltransferase</span> Enzymes that catalyze acyl group transfer from acetyl-CoA to histones

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 an acetyl group to the histones, genes can be turned on and off. In general, histone acetylation increases gene expression.

Histone H3 is one of the five main histones 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.

Histone H2B is one of the 5 main histone proteins involved in the structure of chromatin in eukaryotic cells. Featuring a main globular domain and long N-terminal and C-terminal tails, H2B is involved with the structure of the nucleosomes.

Histone methylation is a process by which methyl groups are transferred to amino acids of histone proteins that make up nucleosomes, which the DNA double helix wraps around to form chromosomes. Methylation of histones can either increase or decrease transcription of genes, depending on which amino acids in the histones are methylated, and how many methyl groups are attached. Methylation events that weaken chemical attractions between histone tails and DNA increase transcription because they enable the DNA to uncoil from nucleosomes so that transcription factor proteins and RNA polymerase can access the DNA. This process is critical for the regulation of gene expression that allows different cells to express different genes.

The histone code is a hypothesis that the transcription of genetic information encoded in DNA is in part regulated by chemical modifications to histone proteins, primarily on their unstructured ends. Together with similar modifications such as DNA methylation it is part of the epigenetic code. Histones associate with DNA to form nucleosomes, which themselves bundle to form chromatin fibers, which in turn make up the more familiar chromosome. Histones are globular proteins with a flexible N-terminus that protrudes from the nucleosome. Many of the histone tail modifications correlate very well to chromatin structure and both histone modification state and chromatin structure correlate well to gene expression levels. The critical concept of the histone code hypothesis is that the histone modifications serve to recruit other proteins by specific recognition of the modified histone via protein domains specialized for such purposes, rather than through simply stabilizing or destabilizing the interaction between histone and the underlying DNA. These recruited proteins then act to alter chromatin structure actively or to promote transcription. For details of gene expression regulation by histone modifications see table below.

Protein methylation is a type of post-translational modification featuring the addition of methyl groups to proteins. It can occur on the nitrogen-containing side-chains of arginine and lysine, but also at the amino- and carboxy-termini of a number of different proteins. In biology, methyltransferases catalyze the methylation process, activated primarily by S-adenosylmethionine. Protein methylation has been most studied in histones, where the transfer of methyl groups from S-adenosyl methionine is catalyzed by histone methyltransferases. Histones that are methylated on certain residues can act epigenetically to repress or activate gene expression.

H3K27ac is an epigenetic modification to the DNA packaging protein histone H3. It is a mark that indicates acetylation of the lysine residue at N-terminal position 27 of the histone H3 protein.

In epigenetics, proline isomerization is the effect that cis-trans isomerization of the amino acid proline has on the regulation of gene expression. Similar to aspartic acid, the amino acid proline has the rare property of being able to occupy both cis and trans isomers of its prolyl peptide bonds with ease. Peptidyl-prolyl isomerase, or PPIase, is an enzyme very commonly associated with proline isomerization due to their ability to catalyze the isomerization of prolines. PPIases are present in three types: cyclophilins, FK507-binding proteins, and the parvulins. PPIase enzymes catalyze the transition of proline between cis and trans isomers and are essential to the numerous biological functions controlled and affected by prolyl isomerization Without PPIases, prolyl peptide bonds will slowly switch between cis and trans isomers, a process that can lock proteins in a nonnative structure that can affect render the protein temporarily ineffective. Although this switch can occur on its own, PPIases are responsible for most isomerization of prolyl peptide bonds. The specific amino acid that precedes the prolyl peptide bond also can have an effect on which conformation the bond assumes. For instance, when an aromatic amino acid is bonded to a proline the bond is more favorable to the cis conformation. Cyclophilin A uses an "electrostatic handle" to pull proline into cis and trans formations. Most of these biological functions are affected by the isomerization of proline when one isomer interacts differently than the other, commonly causing an activation/deactivation relationship. As an amino acid, proline is present in many proteins. This aids in the multitude of effects that isomerization of proline can have in different biological mechanisms and functions.

H4K20me is an epigenetic modification to the DNA packaging protein Histone H4. It is a mark that indicates the mono-methylation at the 20th lysine residue of the histone H4 protein. This mark can be di- and tri-methylated. It is critical for genome integrity including DNA damage repair, DNA replication and chromatin compaction.

H4K16ac is an epigenetic modification to the DNA packaging protein Histone H4. It is a mark that indicates the acetylation at the 16th lysine residue of the histone H4 protein.

H4K5ac is an epigenetic modification to the DNA packaging protein histone H4. It is a mark that indicates the acetylation at the 5th lysine residue of the histone H4 protein. H4K5 is the closest lysine residue to the N-terminal tail of histone H4. It is enriched at the transcription start site (TSS) and along gene bodies. Acetylation of histone H4K5 and H4K12ac is enriched at centromeres.

H4K8ac, representing an epigenetic modification to the DNA packaging protein histone H4, is a mark indicating the acetylation at the 8th lysine residue of the histone H4 protein. It has been implicated in the prevalence of malaria.

H4K12ac is an epigenetic modification to the DNA packaging protein histone H4. It is a mark that indicates the acetylation at the 12th lysine residue of the histone H4 protein. H4K12ac is involved in learning and memory. It is possible that restoring this modification could reduce age-related decline in memory.

H3K14ac is an epigenetic modification to the DNA packaging protein Histone H3. It is a mark that indicates the acetylation at the 14th lysine residue of the histone H3 protein.

H3K9ac is an epigenetic modification to the DNA packaging protein Histone H3. It is a mark that indicates the acetylation at the 9th lysine residue of the histone H3 protein.

H3K36ac is an epigenetic modification to the DNA packaging protein Histone H3. It is a mark that indicates the acetylation at the 36th lysine residue of the histone H3 protein.

H3K36me2 is an epigenetic modification to the DNA packaging protein Histone H3. It is a mark that indicates the di-methylation at the 36th lysine residue of the histone H3 protein.

References

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