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In biology, histones are highly basic abundant in lysine and arginine residues that are found in eukaryotic cell nuclei and in most Archaea Phylum. They act as spools around which DNA winds to create structural units called . (2025). 9780007221349, HarperCollins. ISBN 9780007221349 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 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 9 micrometers (0.09 mm) of 30 nm diameter chromatin fibers.
There are five families of histones, which are designated H1/H5 (linker histones), H2, H3, and H4 (core histones). The nucleosome core is formed of two H2A-H2B protein dimer and a H3-H4 tetramer. The tight wrapping of DNA around histones, is to a large degree, a result of electrostatic attraction between the positively charged histones and negatively charged phosphate backbone of DNA.
Histones may be chemically modified through the action of enzymes to regulate gene transcription. The most common modifications are the methylation of arginine or lysine residues or the acetylation of lysine. Methylation can affect how other proteins such as transcription factors interact with the nucleosomes. Lysine acetylation eliminates a positive charge on lysine thereby weakening the electrostatic attraction between histone and DNA, resulting in partial unwinding of the DNA, making it more accessible for gene expression.
The core histones all exist as Protein dimer, which are similar in that they all possess the histone fold domain: three alpha helices linked by two loops. It is this helical structure that allows for interaction between distinct dimers, particularly in a head-tail fashion (also called the handshake motif). The resulting four distinct dimers then come together to form one octameric nucleosome core, approximately 63 Angstroms in diameter (a solenoid (DNA)-like particle). Around 146 base pairs (bp) of DNA wrap around this core particle 1.65 times in a left-handed super-helical turn to give a particle of around 100 Angstroms across. The linker histone H1 binds the nucleosome at the entry and exit sites of the DNA, thus locking the DNA into place (1996). 9780915274840, AACC Press. ISBN 9780915274840 and allowing the formation of higher order structure. The most basic such formation is the 10 nm fiber or beads on a string conformation. This involves the wrapping of DNA around nucleosomes with approximately 50 base pairs of DNA separating each pair of (also referred to as linker DNA). Higher-order structures include the 30 nm fiber (forming an irregular zigzag) and 100 nm fiber, these being the structures found in normal cells. During mitosis and meiosis, the condensed are assembled through interactions between nucleosomes and other regulatory proteins.
Histones are subdivided into canonical replication-dependent histones, whose genes are expressed during the S-phase of the cell cycle and replication-independent histone variants, expressed during the whole cell cycle. In mammals, genes encoding canonical histones are typically clustered along chromosomes in 4 different highly-conserved loci, lack and use a stem loop structure at the 3' end instead of a polyA tail. Genes encoding histone variants are usually not clustered, have introns and their mRNAs are regulated with polyA tails. Complex multicellular organisms typically have a higher number of histone variants providing a variety of different functions. Functionally, histone variants contribute to transcriptional control, epigenetic memory, and DNA repair, serving specialized functions beyond nucleosome packaging which plays distinct roles in chromatin dynamics. For example, H2A.Z is enriched at regulatory elements and promoters of actively transcribed genes, where it modulates nucleosome stability and transcription factor binding. In contrast, H3.3, a replacement variant of Histone H3, is associated with active transcription and is preferentially deposited at enhancer elements and transcribed gene bodies. Another critical variant, CENPA, replaces H3 in centromeric nucleosomes, providing a structural foundation essential for chromosome segregation.
Variants also play essential roles in DNA repair. Variants such as H2A.X are phosphorylated at sites of DNA damage, marking regions for recruitment of repair proteins. This modification, commonly referred to as γH2A.X, serves as a key signal in the cellular response to double-strand breaks, facilitating efficient DNA repair processes. Defects in histone variant regulation have been linked to genome instability, a hallmark of many cancers and age-related diseases.
Recent data are accumulating about the roles of diverse histone variants highlighting the functional links between variants and the delicate regulation of organism development. Histone variants proteins from different organisms, their classification and variant specific features can be found in "HistoneDB 2.0 - Variants" database. Several Pseudogene have also been discovered and identified in very close sequences of their respective functional ortholog genes.
The following is a list of human histone proteins, genes and pseudogenes:
| Linker | H1 | H1-1, H1-2, H1-3, H1-4, H1-5, H1-6 | H1-0, H1-7, H1-8, H1-10 | H1-9P, H1-12P |
| Core | H2A | H2AC1, H2AC4, H2AC6, H2AC7, H2AC8, H2AC11, H2AC12, H2AC13, H2AC14, H2AC15, H2AC16, H2AC17, H2AC18, H2AC19, H2AC20, H2AC21, H2AC25 | H2AZ1, H2AZ2, MACROH2A1, MACROH2A2, H2AX, H2AJ, H2AB1, H2AB2, H2AB3, HYPM, H2AL1Q, H2AL3 | H2AC2P, H2AC3P, H2AC5P, H2AC9P, H2AC10P, H2AQ1P, H2AL1MP |
| H2B | H2BC1, H2BC3, H2BC4, H2BC5, H2BC6, H2BC7, H2BC8, H2BC9, H2BC10, H2BC11, H2BC12, H2BC13, H2BC14, H2BC15, H2BC17, H2BC18, H2BC21, H2BC26, H2BC12L | H2BK1, H2BW1, H2BW2, H2BW3P, H2BN1 | H2BC2P, H2BC16P, H2BC19P, H2BC20P, H2BC27P, H2BL1P, H2BW3P, H2BW4P | |
| H3 | H3C1, H3C2, H3C3, H3C4, H3C6, H3C7, H3C8, H3C10, H3C11, H3C12, H3C13, H3C14, H3C15, H3-4 | H3-3A, H3-3B, H3-5, H3-7, H3Y1, H3Y2 , CENPA | H3C5P, H3C9P, H3P16, H3P44 | |
| H4 | H4C1, H4C2, H4C3, H4C4, H4C5, H4C6, H4C7, H4C8, H4C9, H4C11, H4C12, H4C13, H4C14, H4C15 | H4C16 | H4C10P |
Archaeal histone only contains a H3-H4 like dimeric structure made out of a single type of unit. Such dimeric structures can stack into a tall superhelix ("hypernucleosome") onto which DNA coils in a manner similar to nucleosome spools. Only some archaeal histones have tails.
The distance between the spools around which eukaryotic cells wind their DNA has been determined to range from 59 to 70 Å.
In all, histones make five types of interactions with DNA:
The highly basic nature of histones, aside from facilitating DNA-histone interactions, contributes to their water solubility.
Histones are subject to post translational modification by enzymes primarily on their N-terminal tails, but also in their globular domains. Such modifications include methylation, citrullination, acetylation, phosphorylation, SUMO protein, , and ADP-ribosylation. This affects their function of gene regulation.
In general, that are active have less bound histone, while inactive genes are highly associated with histones during interphase.
It has been proposed that core histone proteins are evolutionarily related to the helical part of the extended AAA+ ATPase domain, the C-domain, and to the N-terminal substrate recognition domain of Clp/Hsp100 proteins. Despite the differences in their topology, these three folds share a homologous helix-strand-helix (HSH) motif. It's also proposed that they may have evolved from ribosomal proteins (RPS6/RPS15), both being short and basic proteins.
Archaeal histones may well resemble the evolutionary precursors to eukaryotic histones. Histone proteins are among the most highly conserved proteins in eukaryotes, emphasizing their important role in the biology of the nucleus. In contrast mature sperm cells largely use protamines to package their genomic DNA, most likely because this allows them to achieve an even higher packaging ratio.
There are some variant forms in some of the major classes. They share amino acid sequence homology and core structural similarity to a specific class of major histones but also have their own feature that is distinct from the major histones. These minor histones usually carry out specific functions of the chromatin metabolism. For example, histone H3-like CENPA is associated with only the centromere region of the chromosome. Histone H2A variant H2A.Z is associated with the promoters of actively transcribed genes and also involved in the prevention of the spread of silent heterochromatin. Furthermore, H2A.Z has roles in chromatin for genome stability. Another H2A variant H2A.X is phosphorylated at S139 in regions around double-strand breaks and marks the region undergoing DNA repair. Histone H3.3 is associated with the body of actively transcribed genes.
The common nomenclature of histone modifications is:
So H3K4me1 denotes the monomethylation of the 4th residue (a lysine) from the start (i.e., the N-terminal) of the H3 protein.
Cigarette smokers (about 15% of the US population) are usually addicted to nicotine. 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. 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.
About 7% of the US population is addicted to Alcoholism. 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.
Methamphetamine addiction occurs in about 0.2% of the US population. Chronic methamphetamine use causes methylation of the lysine in position 4 of histone 3 located at the promoters of the c-fos and the C-C chemokine receptor 2 (ccr2) genes, activating those genes in the nucleus accumbens (NAc). c-fos is well known to be important in addiction. The ccr2 gene is also important in addiction, since mutational inactivation of this gene impairs addiction.
One key function of histone chaperones is maintaining a reservoir of histones, regulating their supply to ensure proper chromatin formation. During DNA replication and transcription (biology), histone chaperones such as ASF1 and FACT facilitate nucleosome reassembly, ensuring the preservation of histone modifications that define cellular identity. Moreover, histone chaperones contribute to nucleosome disassembly in response to cellular stress or DNA damage, thereby allowing access to repair machinery.
Histone chaperones also participate in the selective deposition of histone variants, which are functionally distinct from canonical histones. For example, HIRA is a chaperone that specifically deposits the histone variant H3.3, a marker of active chromatin regions. Similarly, CAF-1 is responsible for incorporating H3.1 and H3.2 into newly replicated DNA, highlighting the functional specialization within chaperone networks.
Given their critical roles, misregulation of histone chaperones has been implicated in diseases such as cancer. Aberrant chaperone activity can lead to improper histone deposition, genome instability, and altered gene expression, contributing to tumorigenesis. Current research is exploring histone chaperones as potential therapeutic targets, particularly in cancers characterized by disrupted chromatin landscapes.
Histone chaperones play a crucial role in responding to DNA damage by regulating chromatin accessibility. For example, in response to double strand breaks, chaperones such as FACT and ASF1 help disassemble nucleosomes at damage sites, allowing repair factors to access the lesion. Once repair is completed, these chaperones facilitate the reassembly of Nucleosome, restoring chromatin structure and ensuring epigenetic information is maintained.
In addition to their role in genome stability, histone chaperones contribute to epigenetic inheritance. During cell division, chromatin states must be faithfully propagated to daughter cells. Chaperones help distribute parental histones onto newly synthesized DNA strands, preserving histone modifications and ensuring continuity of cellular identity. Disruptions in these processes can lead to epigenetic abnormalities associated with developmental disorders.
In the early 1960s, before the types of histones were known and before histones were known to be highly conserved across taxonomically diverse organisms, James F. Bonner and his collaborators began a study of these proteins that were known to be tightly associated with the DNA in the nucleus of higher organisms. Bonner and his postdoctoral fellow Ru Chih C. Huang showed that isolated chromatin would not support RNA transcription in the test tube, but if the histones were extracted from the chromatin, RNA could be transcribed from the remaining DNA. Their paper became a citation classic. Paul T'so and James Bonner had called together a World Congress on Histone Chemistry and Biology in 1964, in which it became clear that there was no consensus on the number of kinds of histone and that no one knew how they would compare when isolated from different organisms.James Bonner and Paul T'so (1965) The Nucleohistones. Holden-Day Inc, San Francisco, London, Amsterdam. Bonner and his collaborators then developed methods to separate each type of histone, purified individual histones, compared amino acid compositions in the same histone from different organisms, and compared amino acid sequences of the same histone from different organisms in collaboration with Emil Smith from UCLA. For example, they found Histone IV sequence to be highly conserved between peas and calf thymus. However, their work on the biochemical characteristics of individual histones did not reveal how the histones interacted with each other or with DNA to which they were tightly bound.
Also in the 1960s, Vincent Allfrey and Alfred Mirsky had suggested, based on their analyses of histones, that acetylation and methylation of histones could provide a transcriptional control mechanism, but did not have available the kind of detailed analysis that later investigators were able to conduct to show how such regulation could be gene-specific. Until the early 1990s, histones were dismissed by most as inert packing material for eukaryotic nuclear DNA, a view based in part on the models of Mark Ptashne and others, who believed that transcription was activated by protein-DNA and protein-protein interactions on largely naked DNA templates, as is the case in bacteria.
During the 1980s, Yahli Lorch and Roger Kornberg showed that a nucleosome on a core promoter prevents the initiation of transcription in vitro, and Michael Grunstein demonstrated that histones repress transcription in vivo, leading to the idea of the nucleosome as a general gene repressor. Relief from repression is believed to involve both histone modification and the action of chromatin-remodeling complexes. Vincent Allfrey and Alfred Mirsky had earlier proposed a role of histone modification in transcriptional activation, regarded as a molecular manifestation of epigenetics. Michael Grunstein and David Allis found support for this proposal, in the importance of histone acetylation for transcription in yeast and the activity of the transcriptional activator Gcn5 as a histone acetyltransferase.
The discovery of the H5 histone appears to date back to the 1970s, and it is now considered an isoform of Histone H1.
(2025). 9781118059814, John Wiley & Sons. ISBN 9781118059814 It also appears that the structure of histones has been conserved, as any deleterious mutations would be severely maladaptive. All histones have a highly positively charged N-terminus with many lysine and arginine residues.
Evolution and species distribution
Core histones are found in the nuclei of eukaryote cells and in most phyla, but not in bacteria. The unicellular algae known as were previously thought to be the only eukaryotes that completely lack histones, but later studies showed that their DNA still encodes histone genes. Unlike the core histones, homologs of the lysine-rich linker histone (H1) proteins are found in bacteria, otherwise known as nucleoprotein HC1/HC2.
Function
Compacting DNA strands
Histones act as spools around which DNA winds. This enables the compaction necessary to fit the large of eukaryotes inside cell nuclei: the compacted molecule is 40,000 times shorter than an unpacked molecule.
Chromatin regulation
Histones undergo posttranslational modifications that alter their interaction with DNA and nuclear proteins. The H3 and H4 histones have long tails protruding from the nucleosome, which can be modified at several places. Modifications of the tail include methylation, acetylation, phosphorylation, ubiquitination, SUMOylation, citrullination, and ADP-ribosylation. The core of the histones H2A and H2B can also be modified. Combinations of modifications, known as histone marks, are thought to constitute a code, the so-called "histone code". Histone modifications act in diverse biological processes such as gene regulation, DNA repair, chromosome condensation (mitosis) and spermatogenesis (meiosis).
+ Examples of histone modifications in transcriptional regulation mono-methylation activation activation activation activation activation activation di-methylation repression repression activation tri-methylation activation repression repression activation,
repressionactivation repression acetylation activation activation activation activation activation
Modification
A huge catalogue of histone modifications have been described, but a functional understanding of most is still lacking. Collectively, it is thought that histone modifications may underlie a histone code, whereby combinations of histone modifications have specific meanings. However, most functional data concerns individual prominent histone modifications that are biochemically amenable to detailed study.
Chemistry
Lysine methylation
The addition of one, two, or many methyl groups to lysine has little effect on the chemistry of the histone; methylation leaves the charge of the lysine intact and adds a minimal number of atoms so steric interactions are mostly unaffected. However, proteins containing Tudor, chromo or PHD domains, amongst others, can recognise lysine methylation with exquisite sensitivity and differentiate mono, di and tri-methyl lysine, to the extent that, for some lysines (e.g.: H4K20) mono, di and tri-methylation appear to have different meanings. Because of this, lysine methylation tends to be a very informative mark and dominates the known histone modification functions.
Glutamine serotonylation
Recently it has been shown, that the addition of a serotonin group to the position 5 glutamine of H3, happens in serotonergic cells such as neurons. This is part of the differentiation of the serotonergic cells. This post-translational modification happens in conjunction with the H3K4me3 modification. The serotonylation potentiates the binding of the general transcription factor TFIID to the TATA box.
Arginine methylation
What was said above of the chemistry of lysine methylation also applies to arginine methylation, and some protein domains—e.g., Tudor domains—can be specific for methyl arginine instead of methyl lysine. Arginine is known to be mono- or di-methylated, and methylation can be symmetric or asymmetric, potentially with different meanings.
Arginine citrullination
Enzymes called peptidylarginine deiminases (PADs) hydrolyze the imine group of arginines and attach a keto group, so that there is one less positive charge on the amino acid residue. This process has been involved in the activation of gene expression by making the modified histones less tightly bound to DNA and thus making the chromatin more accessible. PADs can also produce the opposite effect by removing or inhibiting mono-methylation of arginine residues on histones and thus antagonizing the positive effect arginine methylation has on transcriptional activity.
Lysine acetylation
Addition of an acetyl group has a major chemical effect on lysine as it neutralises the positive charge. This reduces electrostatic attraction between the histone and the negatively charged DNA backbone, loosening the chromatin structure; highly acetylated histones form more accessible chromatin and tend to be associated with active transcription. Lysine acetylation appears to be less precise in meaning than methylation, in that histone acetyltransferases tend to act on more than one lysine; presumably this reflects the need to alter multiple lysines to have a significant effect on chromatin structure. The modification includes H3K27ac.
Serine/threonine/tyrosine phosphorylation
Addition of a negatively charged phosphate group can lead to major changes in protein structure, leading to the well-characterised role of phosphorylation in controlling protein function. It is not clear what structural implications histone phosphorylation has, but histone phosphorylation has clear functions as a post-translational modification, and binding domains such as BRCT have been characterised.
Effects on transcription
Most well-studied histone modifications are involved in control of transcription.
Actively transcribed genes
Two histone modifications are particularly associated with active transcription:
Repressed genes
Three histone modifications are particularly associated with repressed genes:
Bivalent promoters
Analysis of histone modifications in embryonic stem cells (and other stem cells) revealed many gene promoters carrying both H3K4Me3 and H3K27Me3, in other words these promoters display both activating and repressing marks simultaneously. This peculiar combination of modifications marks genes that are poised for transcription; they are not required in stem cells, but are rapidly required after differentiation into some lineages. Once the cell starts to differentiate, these bivalent promoters are resolved to either active or repressive states depending on the chosen lineage.
Other functions
DNA damage repair
Marking sites of DNA damage is an important function for histone modifications. Without a repair marker, DNA would get destroyed by damage accumulated from sources such as the ultraviolet radiation of the sun.
Chromosome condensation
Addiction
Epigenetic modifications of histone tails in specific regions of the brain are of central importance in addictions. (2025). 9780128009772, Academic Press. ISBN 9780128009772 Once particular epigenetic alterations occur, they appear to be long lasting "molecular scars" that may account for the persistence of addictions.
Histone Chaperones
Histone chaperones (biology) are specialized proteins that assist in the proper handling, transport, and assembly of histones, preventing their aggregation and ensuring their appropriate deposition onto DNA. These proteins play a crucial role in regulating nucleosome assembly and disassembly, influencing transcriptional activity, DNA replication, and repair. Unlike enzymatic chromatin remodeling, histone chaperones function by binding histones in a regulated manner, modulating chromatin structure without direct catalytic activity.
Chaperone Networks
The coordinated action of multiple histone chaperones forms an intricate network responsible for histone transport, Chromatin assembly factor 1, and genome maintenance. Chaperone networks facilitate the transport of histones which are synthesized in the cytoplasm and must be escorted to the cell nucleus. This network ensures histones are deposited at the appropriate genomic locations, maintaining chromatin integrity and function.
Synthesis
The first step of chromatin structure duplication is the synthesis of histone proteins: H1, H2A, H2B, H3, H4. These proteins are synthesized during S phase of the cell cycle. There are different mechanisms which contribute to the increase of histone synthesis.
Yeast
Yeast carry one or two copies of each histone gene, which are not clustered but rather scattered throughout chromosomes. Histone gene transcription is controlled by multiple gene regulatory proteins such as transcription factors which bind to histone promoter regions. In budding yeast, the candidate gene for activation of histone gene expression is SBF. SBF is a transcription factor that is activated in late G1 phase, when it dissociates from its repressor Whi5. This occurs when Whi5 is phosphorylated by Cdc8 which is a G1/S Cdk. Suppression of histone gene expression outside of S phases is dependent on Hir proteins which form inactive chromatin structure at the locus of histone genes, causing transcriptional activators to be blocked.
Metazoan
In the increase in the rate of histone synthesis is due to the increase in processing of pre-mRNA to its mature form as well as decrease in mRNA degradation; this results in an increase of active mRNA for translation of histone proteins. The mechanism for mRNA activation has been found to be the removal of a segment of the 3' end of the mRNA strand, and is dependent on association with stem-loop binding protein (SLBP). SLBP also stabilizes histone mRNAs during S phase by blocking degradation by the 3'hExo nuclease. SLBP levels are controlled by cell-cycle proteins, causing SLBP to accumulate as cells enter S phase and degrade as cells leave S phase. SLBP are marked for degradation by phosphorylation at two threonine residues by cyclin dependent kinases, possibly cyclin A/ cdk2, at the end of S phase. Metazoans also have multiple copies of histone genes clustered on chromosomes which are localized in structures called Cajal bodies as determined by genome-wide chromosome conformation capture analysis (4C-Seq).
Link between cell-cycle control and synthesis
Nuclear protein Ataxia-Telangiectasia (NPAT), also known as nuclear protein coactivator of histone transcription, is a transcription factor which activates histone gene transcription on chromosomes 1 and 6 of human cells. NPAT is also a substrate of cyclin E-Cdk2, which is required for the transition between G1 phase and S phase. NPAT activates histone gene expression only after it has been phosphorylated by the G1/S-Cdk cyclin E-Cdk2 in early S phase. This shows an important regulatory link between cell-cycle control and histone synthesis.
History
Histones were discovered in 1884 by Albrecht Kossel. The word "histone" dates from the late 19th century and is derived from the German word "Histon", a word itself of uncertain origin, perhaps from Ancient Greek ἵστημι (hístēmi, “make stand”) or ἱστός (histós, “loom”).
See also
External links
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