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Schematic representation of the assembly of the core histones into the nucleosome

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.[1][2] 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 9 micrometers (0.009 mm) of 30 nm diameter chromatin fibers.[3]

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 dimers 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.

Classes and variants

[edit]
Histone heterooctamer (H3,H4,H2A,H2B) + DNA fragment, frog

Five major families of histone proteins exist: H1/H5, H2A, H2B, H3, and H4.[2][4][5][6] Histones H2A, H2B, H3 and H4 are known as the core or nucleosomal histones, while histones H1/H5 are known as the linker histones.

The core histones all exist as dimers, 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).[7] 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.[8] The linker histone H1 binds the nucleosome at the entry and exit sites of the DNA, thus locking the DNA into place[9] 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 nucleosomes (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 chromosomes 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 introns 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.[10] 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.[11]

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.[12]

Recent data are accumulating about the roles of diverse histone variants highlighting the functional links between variants and the delicate regulation of organism development.[13] Histone variants proteins from different organisms, their classification and variant specific features can be found in "HistoneDB 2.0 - Variants" database.[14][15] Several pseudogenes have also been discovered and identified in very close sequences of their respective functional ortholog genes.[16][17]

The following is a list of human histone proteins, genes and pseudogenes:[10]

Super family Family Replication-dependent genes Replication-independent genes 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, H2AP, 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

Structure

[edit]
Steps in nucleosome assembly

The nucleosome core is formed of two H2A-H2B dimers and a H3-H4 tetramer, forming two nearly symmetrical halves by tertiary structure (C2 symmetry; one macromolecule is the mirror image of the other).[8] The H2A-H2B dimers and H3-H4 tetramer also show pseudodyad symmetry. The 4 'core' histones (H2A, H2B, H3 and H4) are relatively similar in structure and are highly conserved through evolution, all featuring a 'helix turn helix turn helix' motif (DNA-binding protein motif that recognize specific DNA sequence). They also share the feature of long 'tails' on one end of the amino acid structure - this being the location of post-translational modification (see below).[18]

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.[19] Only some archaeal histones have tails.[20]

The distance between the spools around which eukaryotic cells wind their DNA has been determined to range from 59 to 70 Å.[21]

In all, histones make five types of interactions with DNA:

  • Salt bridges and hydrogen bonds between side chains of basic amino acids (especially lysine and arginine) and phosphate oxygens on DNA
  • Helix-dipoles form alpha-helixes in H2B, H3, and H4 cause a net positive charge to accumulate at the point of interaction with negatively charged phosphate groups on DNA
  • Hydrogen bonds between the DNA backbone and the amide group on the main chain of histone proteins
  • Nonpolar interactions between the histone and deoxyribose sugars on DNA
  • Non-specific minor groove insertions of the H3 and H2B N-terminal tails into two minor grooves each on the DNA molecule

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.[22][23] Such modifications include methylation, citrullination, acetylation, phosphorylation, SUMOylation, ubiquitination, and ADP-ribosylation. This affects their function of gene regulation.

In general, genes that are active have less bound histone, while inactive genes are highly associated with histones during interphase.[24] It also appears that the structure of histones has been evolutionarily 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

[edit]

Core histones are found in the nuclei of eukaryotic cells and in most Archaeal phyla, but not in bacteria.[20] The unicellular algae known as dinoflagellates were previously thought to be the only eukaryotes that completely lack histones,[25] but later studies showed that their DNA still encodes histone genes.[26] Unlike the core histones, homologs of the lysine-rich linker histone (H1) proteins are found in bacteria, otherwise known as nucleoprotein HC1/HC2.[27]

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.[18] It's also proposed that they may have evolved from ribosomal proteins (RPS6/RPS15), both being short and basic proteins.[28]

Archaeal histones may well resemble the evolutionary precursors to eukaryotic histones.[20] Histone proteins are among the most highly conserved proteins in eukaryotes, emphasizing their important role in the biology of the nucleus.[2]: 939  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.[29]

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.[30] Furthermore, H2A.Z has roles in chromatin for genome stability.[31] Another H2A variant H2A.X is phosphorylated at S139 in regions around double-strand breaks and marks the region undergoing DNA repair.[32] Histone H3.3 is associated with the body of actively transcribed genes.[33]

Function

[edit]
Basic units of chromatin structure

Compacting DNA strands

[edit]

Histones act as spools around which DNA winds. This enables the compaction necessary to fit the large genomes of eukaryotes inside cell nuclei: the compacted molecule is 40,000 times shorter than an unpacked molecule.

Transcription

[edit]

The effect of histones on transcription was established already in the late 1980s. Specifically, when histones are mutated or depleted a substantial activation of transcription occurs and is independent of other transcription factors (or suggesting that the latter displace histones).[34]

Chromatin regulation

[edit]
Histone tails and their function in chromatin formation

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 covalently 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".[35][36] Histone modifications act in diverse biological processes such as gene regulation, DNA repair, chromosome condensation (mitosis) and spermatogenesis (meiosis).[37]

The common nomenclature of histone modifications is:

  • The name of the histone (e.g., H3)
  • The single-letter amino acid abbreviation (e.g., K for Lysine) and the amino acid position in the protein
  • The type of modification (Me: methyl, P: phosphate, Ac: acetyl, Ub: ubiquitin)
  • The number of modifications (only Me is known to occur in more than one copy per residue. 1, 2 or 3 is mono-, di- or tri-methylation)

So H3K4me1 denotes the monomethylation of the 4th residue (a lysine) from the start (i.e., the N-terminal) of the H3 protein.

Examples of histone modifications in transcriptional regulation
Type of
modification 		Histone
H3K4 H3K9 H3K14 H3K27 H3K79 H3K36 H4K20 H2BK5 H2BK20
mono-methylation activation[38] activation[39] activation[39] activation[39][40] activation[39] activation[39]
di-methylation repression[41] repression[41] activation[40]
tri-methylation activation[42] repression[39] repression[39] activation,[40]
repression[39] 		activation repression[43]
acetylation activation[44] activation[42] activation[42] activation[45] activation

Modification

[edit]
Schematic representation of histone modifications. Based on Rodriguez-Paredes and Esteller, Nature, 2011.

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

[edit]

Lysine methylation

[edit]

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

[edit]

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.[46]

Arginine methylation

[edit]

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

[edit]

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.[47] 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.[48]

Lysine acetylation

[edit]

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

[edit]

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

[edit]

Histone modifications are involved in control of transcription.

Actively transcribed genes

[edit]

Two histone modifications are particularly associated with active transcription:

Trimethylation of H3 lysine 4 (H3K4me3)
This trimethylation occurs at the promoter of active genes[49][50][51] and is performed by the COMPASS complex.[52][53][54] Despite the conservation of this complex and histone modification from yeast to mammals, it is not entirely clear what role this modification plays. However, it is an excellent mark of active promoters and the level of this histone modification at a gene's promoter is broadly correlated with transcriptional activity of the gene. The formation of this mark is tied to transcription in a rather convoluted manner: early in transcription of a gene, RNA polymerase II undergoes a switch from initiating' to 'elongating', marked by a change in the phosphorylation states of the RNA polymerase II C terminal domain (CTD). The same enzyme that phosphorylates the CTD also phosphorylates the Rad6 complex,[55][56] which in turn adds a ubiquitin mark to H2B K123 (K120 in mammals).[57] H2BK123Ub occurs throughout transcribed regions, but this mark is required for COMPASS to trimethylate H3K4 at promoters.[58][59]
Trimethylation of H3 lysine 36 (H3K36me3)
This trimethylation occurs in the body of active genes and is deposited by the methyltransferase Set2.[60] This protein associates with elongating RNA polymerase II, and H3K36Me3 is indicative of actively transcribed genes.[61] H3K36Me3 is recognised by the Rpd3 histone deacetylase complex, which removes acetyl modifications from surrounding histones, increasing chromatin compaction and repressing spurious transcription.[62][63][64] Increased chromatin compaction prevents transcription factors from accessing DNA, and reduces the likelihood of new transcription events being initiated within the body of the gene. This process therefore helps ensure that transcription is not interrupted.

Repressed genes

[edit]

Three histone modifications are particularly associated with repressed genes:

Trimethylation of H3 lysine 27 (H3K27me3)
This histone modification is deposited by the polycomb complex PRC2.[65] It is a clear marker of gene repression,[66] and is likely bound by other proteins to exert a repressive function. Another polycomb complex, PRC1, can bind H3K27me3[66] and adds the histone modification H2AK119Ub which aids chromatin compaction.[67][68] Based on this data it appears that PRC1 is recruited through the action of PRC2, however, recent studies show that PRC1 is recruited to the same sites in the absence of PRC2.[69][70]
Di and tri-methylation of H3 lysine 9 (H3K9me2/3)
H3K9me2/3 is a well-characterised marker for heterochromatin, and is therefore strongly associated with gene repression. The formation of heterochromatin has been best studied in the yeast Schizosaccharomyces pombe, where it is initiated by recruitment of the RNA-induced transcriptional silencing (RITS) complex to double stranded RNAs produced from centromeric repeats.[71] RITS recruits the Clr4 histone methyltransferase which deposits H3K9me2/3.[72] This process is called histone methylation. H3K9Me2/3 serves as a binding site for the recruitment of Swi6 (heterochromatin protein 1 or HP1, another classic heterochromatin marker)[73][74] which in turn recruits further repressive activities including histone modifiers such as histone deacetylases and histone methyltransferases.[75]
Trimethylation of H4 lysine 20 (H4K20me3)
This modification is tightly associated with heterochromatin,[76][77] although its functional importance remains unclear. This mark is placed by the Suv4-20h methyltransferase, which is at least in part recruited by heterochromatin protein 1.[76]

Bivalent promoters

[edit]

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.[78]

Other functions

[edit]

DNA damage repair

[edit]

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.

Phosphorylation of H2AX at serine 139 (γH2AX)
Phosphorylated H2AX (also known as gamma H2AX) is a marker for DNA double strand breaks,[79] and forms part of the response to DNA damage.[32][80] H2AX is phosphorylated early after detection of DNA double strand break, and forms a domain extending many kilobases either side of the damage.[79][81][82] Gamma H2AX acts as a binding site for the protein MDC1, which in turn recruits key DNA repair proteins[83] (this complex topic is well reviewed in[84]) and as such, gamma H2AX forms a vital part of the machinery that ensures genome stability.
Acetylation of H3 lysine 56 (H3K56Ac)
H3K56Acx is required for genome stability.[85][86] H3K56 is acetylated by the p300/Rtt109 complex,[87][88][89] but is rapidly deacetylated around sites of DNA damage. H3K56 acetylation is also required to stabilise stalled replication forks, preventing dangerous replication fork collapses.[90][91] Although in general mammals make far greater use of histone modifications than microorganisms, a major role of H3K56Ac in DNA replication exists only in fungi, and this has become a target for antibiotic development.[92]
Trimethylation of H3 lysine 36 (H3K36me3)
H3K36me3 has the ability to recruit the MSH2-MSH6 (hMutSα) complex of the DNA mismatch repair pathway.[93] Consistently, regions of the human genome with high levels of H3K36me3 accumulate less somatic mutations due to mismatch repair activity.[94]

Chromosome condensation

[edit]
Phosphorylation of H3 at serine 10 (phospho-H3S10)
The mitotic kinase aurora B phosphorylates histone H3 at serine 10, triggering a cascade of changes that mediate mitotic chromosome condensation.[95][96] Condensed chromosomes therefore stain very strongly for this mark, but H3S10 phosphorylation is also present at certain chromosome sites outside mitosis, for example in pericentric heterochromatin of cells during G2. H3S10 phosphorylation has also been linked to DNA damage caused by R-loop formation at highly transcribed sites.[97]
Phosphorylation H2B at serine 10/14 (phospho-H2BS10/14)
Phosphorylation of H2B at serine 10 (yeast) or serine 14 (mammals) is also linked to chromatin condensation, but for the very different purpose of mediating chromosome condensation during apoptosis.[98][99] This mark is not simply a late acting bystander in apoptosis as yeast carrying mutations of this residue are resistant to hydrogen peroxide-induced apoptotic cell death.

Addiction

[edit]

Epigenetic modifications of histone tails in specific regions of the brain are of central importance in addictions.[100][101][102] Once particular epigenetic alterations occur, they appear to be long lasting "molecular scars" that may account for the persistence of addictions.[100]

Cigarette smokers (about 15% of the US population) are usually addicted to nicotine.[103] 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.[104] 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.[105][106]

About 7% of the US population is addicted to alcohol. 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.[107]

Methamphetamine addiction occurs in about 0.2% of the US population.[108] 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).[109] c-fos is well known to be important in addiction.[110] The ccr2 gene is also important in addiction, since mutational inactivation of this gene impairs addiction.[109]

Histone chaperones

[edit]

Histone chaperones 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.[111]

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, 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.[11]

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.[111]

Chaperone networks

[edit]

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.[112]

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 nucleosomes, restoring chromatin structure and ensuring epigenetic information is maintained.[113]

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.[112]

Synthesis

[edit]

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

[edit]

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.[114] 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.[115][116]

Metazoan

[edit]

In metazoans 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).[117] SLBP also stabilizes histone mRNAs during S phase by blocking degradation by the 3'hExo nuclease.[118] 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.[119] 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).[120]

[edit]

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.[121] This shows an important regulatory link between cell-cycle control and histone synthesis.

History

[edit]

Histones were discovered in 1884 by Albrecht Kossel.[122] 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").

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.[123] 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.[124] Their paper became a citation classic.[125] 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.[126][123] 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.[127] For example, they found Histone IV sequence to be highly conserved between peas and calf thymus.[127] 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.[126]

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.[128] 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[129] showed that a nucleosome on a core promoter prevents the initiation of transcription in vitro, and Michael Grunstein[130] 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,[131] regarded as a molecular manifestation of epigenetics. Michael Grunstein[132] and David Allis[133] 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,[134] and it is now considered an isoform of Histone H1.[2][4][5][6]

See also

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References

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Histone

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Histones are a family of small, basic proteins that serve as the primary structural components of chromatin in eukaryotic cells, enabling the compact packaging of DNA within the nucleus while facilitating essential cellular processes such as gene regulation, replication, and repair. These proteins are evolutionarily ancient, tracing their origins to the last universal common ancestor (LUCA) and predating the emergence of eukaryotic chromatin, with remarkable sequence conservation across species that underscores their fundamental biological importance. Core histones, consisting of two copies each of H2A, H2B, H3, and H4, assemble into an octameric core around which approximately 147 base pairs of DNA wrap in 1.65 left-handed superhelical turns to form the nucleosome, the basic repeating unit of chromatin. The linker histone H1 binds to the DNA between nucleosomes, further stabilizing higher-order chromatin folding and contributing to chromosome condensation during mitosis. Beyond their structural roles, histones are subject to a diverse array of post-translational modifications (PTMs), including , , , and ubiquitination, primarily on their flexible N-terminal tails, which collectively form the "histone code" that dynamically influences accessibility and . Histone variants, such as H2A.Z, H3.3, and centromeric CENP-A, introduce functional diversity by incorporating into specific genomic regions to promote processes like transcriptional activation, , or assembly. In addition to their nuclear functions, histones exhibit extranuclear roles, including antimicrobial activity in innate immunity through the formation of (NETs) and modulation of inflammation, thrombosis, and even metabolic regulation via enzymatic activities like copper reduction by H3-H4 complexes. The interplay of histone variants, PTMs, and interactions with DNA and other proteins not only ensures genome stability but also underpins epigenetic , allowing cells to maintain differentiated states across divisions without altering the underlying DNA sequence. Dysregulation of histone modifications and variants has been implicated in diseases ranging from cancer to neurodegenerative disorders, highlighting their critical role in health and .

Molecular Structure and Classes

Core Histone Composition

Core histones are the primary protein components that form the structural foundation of the , consisting of four classes: H2A, H2B, H3, and H4, with each present in two copies to assemble the . These core histones, along with the linker , constitute the five main histone classes in eukaryotes, where H1 binds externally to facilitate higher-order folding. The core histones are small, highly basic proteins characterized by a central globular domain and flexible N-terminal tails that protrude from the core. The globular domains of H2A, H2B, H3, and H4 each feature the conserved histone fold motif, a structure comprising three α-helices (α1, α2, and α3) connected by two short loops (L1 and L2), which mediates heterodimerization—specifically, H2A with H2B and H3 with H4. This motif enables the stable packing of dimers into the octameric core. The N-terminal tails, which are unstructured and rich in positively charged residues, extend outward and interact with DNA, influencing chromatin dynamics. In terms of composition, core histones are enriched in basic residues such as and , comprising a significant portion of their sequences to facilitate electrostatic interactions with the negatively charged phosphate backbone; for instance, 16 (Lys16) in histone H4 plays a critical role in these charge-based contacts. They exhibit low levels of acidic and hydrophobic , enhancing their and DNA-binding affinity. Molecular weights of these proteins are relatively uniform: H3 and H4 range from approximately 11 to 15 kDa, while H2A and H2B are around 14 kDa each.

Histone Octamer Assembly

The assembly of the begins with the formation of heterodimers between core histones. Histones H3 and H4 pair to form H3-H4 heterodimers through hydrophobic and electrostatic interactions primarily involving their conserved histone fold domains, which consist of a long α-helix flanked by shorter helices and loops. Similarly, H2A and H2B form H2A-H2B heterodimers via analogous histone fold interactions, creating stable dimeric units that serve as building blocks for higher-order structures. These dimers then associate hierarchically to construct the octamer. Two H3-H4 heterodimers interact via fourfold symmetric interfaces at their C-terminal helical regions to form the central (H3-H4)2 tetramer, which adopts an elongated, saddle-shaped conformation capable of binding DNA. This tetramer provides the structural core, with the two H2A-H2B heterodimers subsequently docking onto its flanks through contacts involving the H2A acidic patch and H4 residues, completing the octameric assembly. The resulting octamer is a disk-like protein complex approximately 65 Å in diameter and 57 Å high, featuring a central channel approximately 20 Å wide that accommodates the minor groove of DNA. In the context of nucleosome formation, approximately 147 base pairs of DNA wrap around the histone octamer in 1.65 left-handed superhelical turns, establishing specific histone-DNA contacts at 14 distinct sites along the superhelix. These interactions, revealed in high-resolution crystal structures, involve arginine residues from the histones inserting into the DNA minor groove, stabilizing the wrap while the saddle-shaped H3-H4 tetramer positions the DNA entry and exit points.

Variant Forms

Histone variants represent specialized, non-canonical forms of the core histones that diverge in sequence, leading to distinct structural properties and functional roles within . These variants are incorporated into nucleosomes in a replication-independent manner, often via dedicated chaperones, to modulate chromatin dynamics and introduce diversity beyond the standard . While core histones are ubiquitously expressed, variants are typically tissue- or context-specific, enabling fine-tuned responses to cellular needs such as or cell differentiation. Among H2A variants, H2A.X plays a key role in DNA damage repair by facilitating the recruitment of repair machinery through at serine 139, marking sites of double-strand breaks; it differs from canonical H2A by a unique C-terminal SQ motif and is present in about 10% of s. MacroH2A contributes to transcription repression and compaction, featuring a large non-histone macrodomain that stabilizes s and inhibits histone ; its N-terminal domain shares approximately 64% similarity with H2A, while the C-terminal extension promotes formation. H2A.Z promotes transcriptional activation and instability, often enriched at promoters; it incorporates into s to lower the energy barrier for binding and is involved in both activation and repression contexts. H2B variants are less diverse but include cell cycle- and tissue-specific forms. H2B.1, also known as testis-specific H2B, exhibits seven differences in its histone-fold domain, reducing nucleosome stability and supporting during ; it is expressed in a -dependent manner in certain contexts. TS H2B (testis-specific H2B) aids in the transition from histones to protamines during maturation, sharing 89% homology with canonical H2B but with a unique N-terminal region that facilitates this specialized restructuring. For H3 variants, H3.3 is associated with transcriptionally active genomic regions, deposited replication-independently at and bodies; it differs from canonical H3 by five key residues, including serine 31, which influences stability and accessibility. CENP-A serves as a centromere-specific marker, essential for assembly and segregation; its histone-fold domain shows about 50% conservation with H3, forming more relaxed that wrap only 121 base pairs of DNA. H3t, a testis-specific variant, promotes destabilization during , differing from H3.1 by four residues that enhance fluidity in germ cells. H1 variants, known as linker histones, further diversify chromatin organization. H1.0 is enriched in constitutive heterochromatin and differentiated tissues, correlating with repressive marks like H3K27me3 to maintain stable, compact chromatin structures; it accumulates in non-dividing cells with aging. H1t is testis-specific, supporting in by targeting repetitive elements and facilitating packaging. Sequence divergences among variants often occur in critical regions like the acidic patch or loops, altering interactions. For instance, H2A.Z exhibits approximately 50% sequence divergence from canonical H2A in the acidic patch and L1 loop, which reduces stability and enhances accessibility compared to the more rigid .

Evolutionary Distribution

Conservation in Eukaryotes

Histones exhibit a high degree of sequence and structural conservation across eukaryotic lineages, reflecting their essential role in organization. The core histones H3 and H4 are particularly well-preserved, with H3 in Saccharomyces cerevisiae sharing approximately 90% sequence identity with H3.1 and H3.3. Across a broad sampling of eukaryotic genomes, the histone fold domains of H3 and H4 show average identities of 92% and 93%, respectively, to human references. Critical residues within these domains, such as those involved in dimerization and octamer assembly, are nearly invariant, ensuring structural stability essential for formation. In contrast, H2A and H2B display preservation primarily in their core domains, with yeast-human identities of about 72% for H2A and 67% for H2B. Their N-terminal tails exhibit greater sequence variability, yet retain key motifs that enable post-translational modifications and interactions with regulatory proteins. This pattern of conservation in structural cores versus flexibility in regulatory tails highlights evolutionary optimization for maintaining integrity while allowing adaptive responses. Phylogenetic evidence confirms that core histones are present in all eukaryotes but absent in prokaryotes, indicating their alongside the eukaryotic domain roughly 2 billion years ago. Although histone-like proteins exist in , the full complement of eukaryotic H2A, H2B, H3, and H4 represents a defining tied to the last eukaryotic common ancestor. This widespread conservation underpins a universal nucleosome architecture, facilitating consistent DNA wrapping, compaction, and baseline accessibility mechanisms throughout eukaryotic evolution. Such preservation enables functional interchangeability, as human histones can reconstitute chromatin in yeast systems despite divergence.

Variations Across Species

Histones exhibit notable variations across species, particularly in non-eukaryotic domains and specialized eukaryotic lineages, reflecting adaptations to diverse genomic architectures. In archaea, histones are primarily H3-like proteins that form obligate homodimers, which further assemble into tetramers rather than the hetero-octamers seen in eukaryotes. These tetramers bind and wrap approximately 40–90 base pairs of DNA per unit, organizing it into nucleosome-like structures known as hypernucleosomes, with DNA coiled in a left-handed superhelix similar to eukaryotic nucleosomes but with greater flexibility in wrapping length. This archaeal system represents a primitive form of chromatin compaction, and histone-like proteins in Asgard archaea, the closest prokaryotic relatives to eukaryotes, provide evidence for a pre-eukaryotic origin of histone-based genome organization. Among protists, histone variants show significant divergence tailored to unique nuclear processes. For instance, in the kinetoplastid parasite , the variant histone H3.V features a divergent N-terminal tail compared to canonical H3, which is enriched at telomeres and transcription termination sites, contributing to specialized boundaries in polycistronic units. Similar adaptations occur in other protists, such as Trichomonas vaginalis, where certain H3 variants possess N-terminal extensions that localize to distinct nuclear compartments, highlighting protist-specific modifications for compartmentalized genome regulation. In , histone variants have evolved to support developmental and environmental responses unique to sessile organisms. The plant-specific H2A variant H2A.W serves as a hallmark of , promoting chromatin condensation and in pericentromeric regions, which helps maintain stability and silence transposable elements. This variant, absent in animals and fungi, co-evolved with development and is implicated in regulating networks, including those involved in biogenesis through heterochromatin-mediated repression. Within the animal kingdom, linker histone H1 displays the greatest sequence variability among histone classes, with H4 showing the least divergence across metazoans, underscoring H1's role in fine-tuning dynamics. In , such as Chironomus thummi thummi, specialized H1 variants containing inserted lysine-alanine-proline (KAP) motifs are enriched in polytene chromosomes of salivary glands, facilitating extreme compaction during larval development without . These insect-specific H1 forms contrast with more conserved core histones, enabling adaptations to polytenization and tissue-specific puffing. Additionally, recent studies have identified self-assembling viral histones as potential evolutionary intermediates between archaeal histone homologs and the complex eukaryotic nucleosome, suggesting viruses played a role in the transition to modern chromatin structures.

Primary Functions

DNA Compaction into Chromatin

Histones play a central role in the initial packaging of eukaryotic DNA by forming nucleosomes, the fundamental units of chromatin. The nucleosome core particle consists of approximately 147 base pairs (bp) of DNA wrapped in a left-handed superhelix around a histone octamer composed of two copies each of histones H2A, H2B, H3, and H4. This wrapping occurs in about 1.65 turns, effectively reducing the linear length of the DNA by a factor of roughly 7, from an extended double helix to a more compact structure. The interaction is primarily driven by electrostatic forces, where the positively charged lysine and arginine residues in the histone cores neutralize the negatively charged phosphate backbone of DNA, facilitating tight binding without covalent linkages. Beyond the core, segments of 20 to 80 bp connect adjacent , forming a "beads-on-a-string" structure that represents the primary level of organization. These arrays further fold into the 30 nm fiber, a secondary structure stabilized by the , which binds to the entry and exit points of the DNA on the and the itself. Two main models describe this folding: the model, proposing a one-start coil of with bent , and the model, featuring a two-start with more straight connecting on alternating sides. Both models achieve additional compaction, increasing the overall packing density while maintaining flexibility for cellular processes. At higher orders, the 30 nm fibers organize into loops anchored to protein scaffolds, such as those involving non-histone proteins like topoisomerase II and scaffold/matrix attachment regions, which further condense the structure into domains and eventually territories within the nucleus. This hierarchical folding culminates in a total compaction ratio of approximately 10,000-fold, transforming the 2-meter-long into the micrometer-scale observable during . Electrostatic interactions remain crucial throughout these levels, as the cumulative neutralization of DNA charges by histone positives, augmented by divalent cations like magnesium, promotes fiber stability and prevents repulsion between negatively charged DNA segments.

Nucleosome Positioning and Stability

Nucleosome positioning is influenced by intrinsic properties of the DNA sequence, which determine the preferential locations for binding. Certain sequence motifs, such as periodically spaced TA dinucleotides every 10 base pairs, enhance DNA bendability and thereby favor nucleosome formation by facilitating the wrapping of DNA around the histone core. This rotational positioning code arises from the structural preferences of DNA, where AA, TT, and TA dinucleotides align with minor grooves facing inward toward the histones, stabilizing the nucleosome through favorable electrostatic and steric interactions. These intrinsic signals contribute to the overall occupancy and precise alignment of nucleosomes along the , particularly in regions without strong extrinsic influences. In contrast, specific DNA sequences act as barriers to nucleosome positioning. Poly(dA:dT) tracts, characterized by their inherent stiffness and narrow minor grooves, strongly resist nucleosome formation due to the high energy required to bend such rigid DNA around the histone octamer. Even short poly(dA:dT) stretches of 16 base pairs significantly reduce nucleosome affinity, leading to nucleosome-depleted regions that promote DNA accessibility. These tracts thus serve as intrinsic determinants that shape chromatin organization by excluding nucleosomes and influencing the spacing between positioned ones. Extrinsic factors, primarily ATP-dependent chromatin remodeling complexes, dynamically adjust nucleosome positions to override or modulate intrinsic signals. The SWI/SNF family of remodelers, for instance, uses to translocate DNA along the , enabling nucleosome sliding over tens of base pairs or eviction to expose underlying DNA sequences. These enzymatic activities ensure adaptive nucleosome placement in response to cellular needs, such as during transcription or replication, by altering local structure without necessarily relying on sequence preferences. Nucleosome stability is maintained through hierarchical interactions within the histone octamer, which can be probed by salt-dependent dissociation assays. The H3-H4 tetramer forms a stable central scaffold that binds DNA tightly, resisting dissociation even at high salt concentrations above 1.4 M NaCl. In comparison, the peripheral H2A-H2B dimers are more labile, dissociating at lower salt levels around 0.5-1 M NaCl, which allows for partial disassembly into hexasomes or tetrasomes before complete octamer disruption. This differential stability underscores the modular nature of the nucleosome, facilitating regulated dynamics while preserving overall chromatin integrity.

Baseline Gene Accessibility

In unmodified chromatin, gene accessibility is fundamentally shaped by the structural organization of nucleosomes, which dictate open and closed states across the genome. Euchromatin, characterized by less condensed and transcriptionally active regions, exhibits lower nucleosome density, allowing greater inherent access to DNA for basal cellular processes such as transcription initiation. In contrast, heterochromatin features higher nucleosome density and more compact packing, resulting in closed states that restrict DNA exposure and suppress gene activity by default. This baseline distinction arises from the intrinsic spacing and stability of nucleosome arrays, independent of regulatory modifications, with euchromatic regions showing lower chromatin density compared to heterochromatic ones. A key feature enabling basal accessibility in promoter regions is the presence of nucleosome-depleted regions (NDRs), typically spanning about 150 base pairs immediately upstream of the transcription start site (TSS). These NDRs maintain low nucleosome occupancy, providing an open platform for sequence-specific factors to bind and facilitate initial gene expression without additional regulatory input. Genome-wide mapping in yeast has revealed that over 90% of promoters harbor such NDRs, underscoring their role in ensuring reliable basal access to DNA in unmodified states. The histone octamer itself imposes intrinsic barriers to accessibility by wrapping approximately 147 base pairs of DNA in 1.65 left-handed superhelical turns, occluding a substantial portion of the DNA surface from direct interaction with cellular machinery. Additionally, the flexible N-terminal tails of core histones protrude from the octamer and can further sterically hinder transcription factor binding to adjacent DNA sequences, reinforcing the closed configuration in densely packed arrays. This default occlusion limits promoter escape and processivity in the absence of positioning signals, as briefly noted in studies of nucleosome arrays. Experimental evidence from micrococcal nuclease sequencing (MNase-seq) on unmodified chromatin confirms these patterns, demonstrating periodic protection of DNA fragments at multiples of the nucleosomal repeat length (about 200 base pairs), indicative of regularly spaced nucleosomes shielding the genome. In such arrays, MNase digestion yields a characteristic laddering effect, with protected regions corresponding to histone-bound DNA and linker regions showing higher susceptibility, thus mapping the baseline accessibility landscape in euchromatic and heterochromatic domains alike.

Post-Translational Modifications

Acetylation and Deacetylation

Histone acetylation involves the covalent addition of acetyl groups to the ε-amino group of lysine residues on the N-terminal tails of core histones, primarily catalyzed by histone acetyltransferases (HATs). These enzymes, such as p300 and CREB-binding protein (CBP), utilize acetyl-coenzyme A (acetyl-CoA) as the acetyl donor in an ATP-independent reaction. The mechanism proceeds via a nucleophilic attack by the lysine side chain on the carbonyl carbon of acetyl-CoA, facilitated by a conserved active site glutamate that acts as a general base to deprotonate the lysine and a tyrosine residue (e.g., Y1467 in p300) that protonates the departing coenzyme A (CoA). This process follows a Theorell-Chance kinetic mechanism, where the substrate transiently associates with an acidic pocket on the enzyme without forming a stable ternary complex. The acetylation neutralizes the positive charge of the lysine residue, reducing the electrostatic affinity between the histone tails and the negatively charged DNA backbone, thereby loosening chromatin structure and promoting nucleosome instability. Key acetylation sites include H3K9, H3K27, and H4K16; for instance, acetylation at H4K16 disrupts higher-order chromatin folding, while H3K9 and H3K27 acetylation marks are associated with euchromatic regions. Enzymatic kinetics for HATs, such as p300/CBP and PCAF, exhibit turnover rates (k_cat) in the range of 10-100 min⁻¹, depending on the substrate peptide (e.g., ~12 min⁻¹ for PCAF on H3 tail peptides), reflecting efficient catalysis under physiological conditions. Deacetylation is mediated by histone deacetylases (HDACs), which hydrolytically remove acetyl groups to restore the positive charge on residues and tighten DNA-histone interactions. HDACs are classified into four groups: class I (HDAC1-3, HDAC8; nuclear, zinc-dependent with strong deacetylase activity), class II (subdivided into IIa: HDAC4,5,7,9; IIb: HDAC6,10; shuttling between nucleus and ), class III (sirtuins SIRT1-7; NAD⁺-dependent), and class IV (HDAC11; zinc-dependent). For example, , a class I , associates with corepressor complexes like Sin3A and NuRD to deacetylate histones, promoting compaction. The zinc-dependent classes (I, II, IV) employ a coordinated by histidines and aspartates to activate a water molecule for nucleophilic attack on the acetyl carbonyl, while class III uses NAD⁺ to generate an ADP-ribose intermediate. HDAC enzymatic rates similarly fall within 10-100 min⁻¹, ensuring dynamic equilibrium with HAT activity.

Methylation Patterns

Histone methylation is a key that occurs primarily on the ε-amino groups of residues and the guanidino groups of residues within the N-terminal tails of core histones, particularly H3 and H4. residues can undergo mono-, di-, or tri-methylation, while residues are typically mono- or di-methylated in either symmetric or asymmetric configurations, leading to a diverse array of patterns that influence structure. These modifications are dynamically regulated and do not alter the positive charge of the histone tails, unlike , but instead introduce steric bulk that facilitates the recruitment of specific reader proteins. The enzymes responsible for depositing methyl groups on residues are histone methyltransferases (HMTs), many of which contain a conserved SET domain that catalyzes the transfer of methyl groups from S-adenosylmethionine (SAM). For instance, , a SET domain-containing HMT and core component of the Polycomb repressive complex 2 (PRC2), specifically catalyzes trimethylation of at 27 (), a mark associated with transcriptional repression. In contrast, methylation is mediated by protein methyltransferases (PRMTs), which are classified into type I (asymmetric dimethylation, e.g., PRMT1) and type II (symmetric dimethylation, e.g., PRMT5) families. A notable example is CARM1 (PRMT4), which methylates at 17 (H3R17), often in conjunction with other modifications to fine-tune accessibility. Prominent methylation sites on histone H3 include , which is enriched at active promoters and correlates with transcriptional activation; , a hallmark of constitutive and ; and , linked to facultative and developmental gene repression. These sites exemplify how states dictate functional outcomes: trimethylation at promotes open , while di- or tri-methylation at H3K9 and H3K27 enforces compact, inaccessible states. The neutral charge of methylated residues allows for selective binding by reader domains, such as the chromodomain of (HP1), which recognizes and stabilizes through multivalent interactions. Reversal of methylation is achieved by demethylases, which fall into two major classes based on their catalytic mechanisms. The (FAD)-dependent amine oxidases, exemplified by -specific demethylase 1A (, also known as LSD1), oxidatively remove mono- and di-methyl groups from residues, such as H3K4me1/2, producing and unmodified .00923-4) In parallel, the JmjC domain-containing demethylases (KDM2–KDM8) utilize Fe(II) and α-ketoglutarate (α-KG) as cofactors in a hydroxylation-dependent mechanism that decarboxylates α-KG to succinate, enabling the removal of all methylation states, including trimethylation, from sites like and H3K27me3.00175-7) This oxidative process ensures the reversibility of patterns, allowing cells to respond to environmental cues.

Phosphorylation and Other Core Modifications

Phosphorylation involves the covalent addition of groups to residues such as serine (Ser), (Thr), or (Tyr) on histone tails or cores, catalyzed by specific kinases. This modification is highly dynamic and reversible, often serving as a signaling mechanism in response to cellular events like or stress. In eukaryotes, histone sites are conserved and site-specific, with fewer documented instances compared to acetylation or . Kinases such as Aurora B target at Ser10 (H3S10ph) during , promoting condensation by displacing (HP1) from H3K9- regions through a phospho-methyl switch mechanism. A prominent example of in stress signaling is the modification of histone variant H2AX at Ser139 (γH2AX), induced by kinases including ataxia-telangiectasia mutated (), ATM- and Rad3-related (ATR), and DNA-dependent (DNA-PK). This mark forms foci at DNA double-strand break sites, amplifying the recruitment of repair machinery and establishing it as a sensitive for genotoxic damage. While γH2AX highlights damage-related phosphorylation, mitotic events like H3S10ph underscore the role of this PTM in regulation. Beyond , other core modifications include ubiquitination, sumoylation, and , which add larger moieties to lysine or acidic residues. Ubiquitination typically occurs as monoubiquitination on at Lys119 (H2AK119ub), mediated by the E3 RING1B within Polycomb repressive complex 1 (PRC1). This mark enforces transcriptional repression at developmental genes by compacting and facilitating H3K27 trimethylation, with RING1B's catalytic activity essential for maintaining Polycomb silencing in embryonic stem cells.30890-1) Sumoylation conjugates small ubiquitin-like modifier (SUMO) proteins to lysine residues on histone tails, generally promoting repressive chromatin environments and enhancing nucleosome stability. On histone H4, sumoylation primarily targets Lys12, which indirectly inhibits acetylation at adjacent sites like Lys14 by steric hindrance or altered enzyme access, thereby reinforcing gene silencing. Similarly, ADP-ribosylation, executed by poly(ADP-ribose) polymerases (PARPs) such as PARP1, attaches ADP-ribose to glutamate (Glu) and aspartate (Asp) residues on histone cores, particularly during genotoxic stress. This modification predominates on Glu/Asp in histones extracted from damaged cells, facilitating transient chromatin decompaction to expose DNA for repair. These modifications exhibit cross-talk, where one PTM influences the deposition or recognition of another. For example, H3S10 sterically hinders the binding of HP1 and other readers to nearby H3K9 methylation sites, reducing their affinity and disrupting integrity during mitotic progression.00472-9) Such interactions ensure coordinated of states without altering the core chemistry of individual marks.

Emerging Modifications

Recent discoveries in histone post-translational modifications (PTMs) have revealed novel events that link cellular directly to epigenetic . Serotonylation, identified in 2019, involves the attachment of serotonin to residues on histone tails, primarily at H3Q5, catalyzed by transglutaminase 2 (TGM2). This modification enhances the binding of the TFIID to H3K4me3-marked promoters, thereby promoting permissive transcription of neuronal genes during cell differentiation. Initial characterizations indicate that serotonylation acts as an epigenetic "permissive" mark, amplifying without altering compaction. Lactylation represents another metabolism-driven PTM, where lactate derived from is transferred to residues, such as H3K18, by the acetyltransferase p300.30845-3) This modification accumulates in response to elevated lactate levels and has been linked to inflammatory responses, with 2024 studies showing elevated H3K18la in fibroblast-like synoviocytes from patients, driving pro-inflammatory . In these contexts, lactylation facilitates accessibility at enhancer regions, connecting glycolytic flux to immune cell . Crotonylation, first described in 2011, involves the addition of crotonyl groups from crotonyl-CoA donors to residues on histones, often at sites overlapping with targets like H3K18 and H4K8.00827-6) This PTM exhibits enhanced binding affinity to reader domains compared to acetylation, promoting open and transcriptional activation in a manner that amplifies expression.00827-6) By 2025, reviews have expanded on its role in metabolic diseases, highlighting how crotonylation dysregulation contributes to lipid accumulation and via altered hepatic regulation. Succinylation and malonylation, emerging in the 2020s, derive from tricarboxylic acid (TCA) cycle intermediates—succinyl-CoA and malonyl-CoA, respectively—and target lysine residues, including H3K122. Succinylation at H3K122, for instance, destabilizes nucleosome structure by introducing a negatively charged acyl group on the histone core, facilitating transcription factor access and gene activation. These modifications are enriched in metabolically active cells and have been characterized as regulators of chromatin dynamics in response to mitochondrial function. Advances in 2025 have emphasized combinatorial profiling of these PTMs, revealing synergistic interactions that fine-tune epigenetic landscapes in development and cancer. High-throughput assays mapping multiple modifications simultaneously have identified co-occurring marks, such as lactylation with succinylation, that drive enhancer activation during embryonic differentiation. In , such profiling has uncovered PTM crosstalk promoting tumor heterogeneity and resistance, with elevated crotonylation correlating to aggressive stem-like states. These insights underscore the potential of integrated PTM analysis for therapeutic targeting in epigenetic disorders.

Regulatory Roles of Modifications

Impact on Transcriptional Activity

Histone post-translational modifications (PTMs) exert a profound influence on transcriptional activity by modulating structure and recruiting regulatory proteins. Active marks such as trimethylation of at 4 (H3K4me3) and lysine 36 (H3K36me3) promote through specific interactions with transcriptional machinery. H3K4me3, enriched at active promoters, facilitates the recruitment of TFIID via the plant homeodomain (PHD) finger of TAF3, which binds directly to this mark, thereby stabilizing the pre-initiation complex and enabling (Pol II) assembly.01079-3) Similarly, H3K36me3, deposited co-transcriptionally by SETD2 in the wake of elongating Pol II, aids in transcription elongation by recruiting factors that restore compaction and prevent cryptic initiation, ensuring processive Pol II movement. Histone , particularly on H3 and H4 tails, further enhances these effects by neutralizing positive charges on s, loosening nucleosome-DNA interactions and opening to promote accessibility for Pol II and associated factors. In contrast, repressive marks like , catalyzed by the Polycomb repressive complex 2 (PRC2), propagate silencing across bodies and intergenic regions, inhibiting Pol II progression and maintaining developmental repression.30336-X) This mark spreads bidirectionally from nucleation sites, compacting and evicting activating factors, with PRC2's affinity for preexisting enabling self-reinforcing silencing domains. often synergizes with , particularly at CpG islands, where the two marks reinforce of active transcription; for instance, recruits methyl-CpG-binding proteins that stabilize deposition, amplifying repression in a combinatorial manner. Such synergy is evident in tumor suppressor , where dual inhibition of these pathways leads to derepression and viral mimicry responses. Bivalent domains, characterized by the co-occurrence of and , are prevalent in embryonic stem cells and poise developmental genes for rapid activation or repression during differentiation. These domains maintain low-level Pol II occupancy without productive elongation, allowing swift resolution upon lineage commitment—H3K4me3 persists at poised promoters while suppresses premature expression. The "readers" of these marks, such as bromodomains for acetylated lysines (e.g., in , which recruits P-TEFb to release paused Pol II) and chromodomains for methylated lysines (e.g., in HP1 for , though CBX proteins read ), translate PTMs into functional outcomes by bridging histones to effectors. Recent models, leveraging profiles of multiple PTMs, predict levels with high accuracy; for example, convolutional neural networks trained on histone mark data from promoters and enhancers forecast transcriptional states across cell types, highlighting combinatorial codes.00259-8) Quantitatively, PTMs significantly alter nucleosome occupancy at promoters, with active marks like and reducing occupancy by 20-50% to facilitate Pol II access, while repressive increases it, stabilizing closed . This dynamic remodeling underscores the combinatorial regulation of transcription, where PTM patterns dictate gene-specific outcomes without relying solely on individual marks.

Role in DNA Damage Response

Histones play a pivotal role in the DNA damage response (DDR) by undergoing specific post-translational modifications (PTMs) that facilitate the detection, signaling, and repair of DNA lesions, such as double-strand breaks (DSBs). One of the earliest and most critical modifications is the phosphorylation of histone H2AX at serine 139 (γ-H2AX), mediated by kinases like ATM and DNA-PK. This modification spreads bidirectionally from the DSB site over distances exceeding 100 kilobases, often up to megabases, forming expansive chromatin domains that amplify the damage signal. The γ-H2AX foci serve as a platform for recruiting mediator proteins, including MDC1 and 53BP1, which further propagate the DDR cascade by stabilizing repair factors at the lesion. This spreading mechanism ensures efficient coordination of repair pathways, with γ-H2AX levels correlating with DSB persistence and repair fidelity. Ubiquitination of at lysines 13 and 15 (H2AK13/15ub), catalyzed by the ligase RNF168, represents another key histone PTM in the DDR, particularly in promoting (HR). RNF168 is recruited to γ-H2AX-modified via its recognition of chains initiated by RNF8, leading to mono-ubiquitination of H2AK13/15 on nucleosomes flanking the DSB. This modification creates a docking site for downstream effectors, such as , which directs HR machinery to the break site during the S/G2 phases of the . H2AK13/15ub thus biases repair toward error-free HR while suppressing alternative in certain contexts, highlighting its role in maintaining genomic stability. Acetylation of histone H4 tails by the Tip60 histone acetyltransferase (HAT) complex is essential for chromatin relaxation and access at DSBs. Tip60 specifically targets lysines 5, 8, 12, and 16 (H4K5/8/12/16ac), promoting the eviction of nucleosomes and recruitment of repair proteins like NBS1 and Ku70/80. This acetylation occurs rapidly post-DSB, often in coordination with the NuA4 complex, and facilitates both HR and non-homologous end joining by opening compacted structures. Studies show that Tip60-dependent H4 acetylation is required for efficient DSB repair, with deficiencies leading to hypersensitivity to genotoxic agents. PARylation by poly(ADP-ribose) polymerase 1 () modifies linker and core histone H2B, inducing electrostatic repulsion that loosens higher-order folding to enhance repair factor accessibility. Upon DSB detection, PARP1 auto-PARylates and transfers poly(ADP-ribose) chains to H1, displacing it from nucleosomes, and to H2B tails, which further decompacts . This transient remodeling creates a permissive environment for downstream DDR proteins, such as XRCC1, and is reversed upon repair completion to restore integrity. PARylation thus acts as an early checkpoint in the DDR. Recent insights from 2025 reveal that histone lactylation, a lactate-derived PTM, enhances access in inflammatory contexts, such as post-myocardial or tumor microenvironments. For instance, lactylation of H3K18 in macrophages promotes reparative by increasing openness, facilitating recruitment of repair factors amid metabolic stress and . This modification links glycolytic shifts in immune cells to improved DSB repair efficiency, underscoring its emerging role in context-specific DDR modulation.

Influence on Chromosome Condensation

Post-translational modifications (PTMs) of core histones are pivotal in orchestrating mitotic condensation, transforming extended into compact structures suitable for faithful segregation. These modifications, including , deacetylation, and ubiquitination, modulate histone-DNA and histone-protein interactions to facilitate higher-order folding, condensin recruitment, and maintenance. By dynamically altering accessibility and scaffold formation, histone PTMs ensure error-free while preventing genomic instability. Phosphorylation of at serine 10 (H3S10ph) and serine 28 (H3S28ph) is mediated by the Aurora B , a key component of the chromosomal passenger complex, and is indispensable for mitotic progression. Aurora B-dependent H3S10ph promotes the recruitment and activation of condensin complexes, which drive axial shortening and lateral compaction of through ATP-dependent loop formation. Concurrently, H3S10ph disrupts the binding of (HP1) to methylated H3K9 by creating a "phospho/methyl switch," thereby displacing HP1 from mitotic to enable global reorganization. Similarly, H3S28ph by Aurora B contributes to at active loci, ensuring uniform compaction. These phosphorylation events correlate directly with the onset of . Deacetylation of histone H4 tails by class I histone deacetylases (HDACs), such as HDAC3 in association with AKAP95, drives the transition from loosely packed 30 nm fibers to rigid, scaffold-bound structures during early . This hypoacetylation neutralizes positive charges on residues, strengthening histone-DNA interactions and facilitating the attachment of non-histone proteins like topoisomerase II. HDAC inhibition disrupts this process, leading to defective architecture and segregation errors. Additionally, monoubiquitination of H2A at 119 (H2AK119ub) by the Polycomb repressive complex 1 (PRC1) sustains pericentromeric stability throughout , repressing satellite repeat transcription and preserving centromeric silencing for proper spindle attachment.00279-9) The temporal dynamics of these PTMs align precisely with mitotic phases: H3 phosphorylation surges at prophase to initiate , persists through , and is reversed by protein phosphatase 1 (PP1) at to permit decondensation and nuclear reformation.00034-9) Involving histone variants, methylation of H4K20 within CENP-A nucleosomes—essential for identity—stabilizes the inner platform, recruiting constitutive centromere-associated network (CCAN) proteins and ensuring microtubule-mediated segregation.00281-0) Specific sites like H3S10 and S28 exemplify the phosphorylation mechanisms underlying these processes.

Histone Chaperones and Biosynthesis

Chaperone-Mediated Assembly

Histone chaperones play a crucial role in nucleosome assembly by binding to newly synthesized histones, shielding their positively charged tails to prevent non-specific aggregation, and facilitating their ordered delivery to DNA or other assembly factors. These proteins ensure the sequential deposition of histone dimers and tetramers, starting with the (H3-H4)₂ tetramer to form tetrasomes, followed by H2A-H2B dimers to complete nucleosomes. This process is essential for maintaining chromatin integrity during replication and repair, avoiding aberrant histone-DNA interactions that could lead to genomic instability. Specific chaperones exhibit preferences for particular histone pairs. ASF1 primarily binds H3-H4 dimers, interacting with the histone fold domain to neutralize charges and deliver them to downstream factors like CAF-1 for replication-coupled assembly. NAP1, in contrast, associates with H2A-H2B dimers, enveloping their surfaces in a manner analogous to DNA binding, which promotes deposition onto tetrasomes while inhibiting premature interactions. FACT, a heterodimeric complex of Spt16 and Pob3, facilitates both eviction and redeposition of H2A-H2B dimers during dynamic processes; it binds these dimers via conserved peptide motifs in its subunits, using acidic regions and aromatic residues to engage H2B's hydrophobic patches and shield charges, thereby reorganizing nucleosome structure without full disassembly. Chaperone networks coordinate multiple histones through hub-like proteins such as sNASP, which uses distinct domains—tetratricopeptide repeats (TPR) for H3-H4 and an acidic patch for linker —to bind and manage soluble histone pools simultaneously, enabling coordinated core and linker histone integration. These hubs facilitate hand-off mechanisms, where chaperones like ASF1 transfer H3-H4 to CAF-1 or remodelers, ensuring efficient assembly pathways. Integration with post-translational modifications further refines this process; for instance, chaperones preferentially handle H4 acetylated at lysines 5 and 12, as this neutralizes tail charges and enhances binding affinity to factors like RbAp46 in the HAT1 complex, promoting timely deposition and maturation.

Synthesis in Model Organisms

In budding yeast (Saccharomyces cerevisiae), a key for eukaryotic , core histone genes exist in two copies each, with the H3-H4 genes encoded by the divergently transcribed pairs HHT1-HHF1 and HHT2-HHF2, and similar organization for H2A-H2B loci.00461-4.pdf) These genes are primarily regulated at the transcriptional level, with expression tightly coupled to S-phase entry through activation of promoters responsive to signals. In metazoan model organisms such as humans and Drosophila melanogaster, replication-dependent (RD) histone genes, which encode the canonical histones required for chromatin assembly during DNA replication, are clustered in tandem arrays. The largest such cluster in humans, designated HIST1, is located on chromosome 6p22.1–6p22.2 and contains approximately 49 functional core histone genes, including multiple copies for H2A, H2B, H3, and H4. In contrast, replication-independent (RI) histone genes, which produce variants like H3.3 for non-replicative deposition, are dispersed throughout the genome and expressed constitutively or in response to specific signals. A distinctive feature of RD histone mRNAs in metazoans is their lack of a poly(A) tail; instead, they terminate in a conserved stem-loop structure within the 3' (UTR), formed by a that is essential for mRNA stability, processing, and degradation. This stem-loop, bound by the stem-loop binding protein (SLBP), replaces signals and coordinates rapid turnover of histone mRNAs at the end of S-phase. During S-phase in both and metazoans, histone mRNA levels surge dramatically to match the demand for new nucleosomes, typically increasing 10- to 30-fold through enhanced transcription and mRNA stabilization. These synthesized histones are subsequently delivered to via dedicated chaperones for assembly.

Cell Cycle Coordination

Histone synthesis is precisely coordinated with the cell cycle to ensure that newly synthesized DNA is promptly packaged into chromatin during S phase, preventing imbalances that could disrupt genome stability. Replication-dependent (RD) histone genes, which encode the majority of canonical histones (H2A, H2B, H3.1, H3.2, and H4), are transcriptionally activated at the G1/S transition and repressed thereafter, aligning production with DNA replication demands. This temporal restriction is enforced through cell cycle checkpoints and regulatory mechanisms that monitor DNA synthesis and histone levels, with excess free histones activating degradation pathways to maintain homeostasis. At the , the transcription factor, in complex with DP1, binds to promoter elements of histone and the NPAT , upregulating their expression to initiate a burst of histone mRNA synthesis. NPAT, itself an target, further activates histone transcription by recruiting histone acetyltransferases to promoters. As progresses, histone mRNA levels peak, but post-S phase, synthesis is abruptly halted: CDK1 in complex with cyclin A phosphorylates the stem-loop binding protein (SLBP) at 61, marking SLBP for ubiquitination and degradation, which destabilizes histone mRNA. This process involves UPF1, an that interacts with SLBP to remodel the mRNP complex and promote rapid 3'-to-5' exonucleolytic decay of histone mRNAs, ensuring no excess accumulation beyond replication needs. Checkpoints, such as the checkpoint, further integrate this by degrading excess histones via the if supply outpaces demand, activating Rad53/CHK1-mediated responses that delay progression until balance is restored. In contrast to RD histones, replication-independent (RI) variants like H3.3 are synthesized constitutively throughout the via transcription by (Pol II), producing polyadenylated mRNAs that lack the stem-loop structure and are not subject to S-phase-specific decay. H3.3 genes are expressed at low basal levels in G1, , and phases, supporting ongoing maintenance outside of replication. Dysregulation of this coordinated synthesis, such as overexpression or depletion of histones, disrupts assembly and leads to through missegregation and genomic instability. Recent studies have linked such imbalances to enhanced proliferation, where excess histone supply promotes tolerance to and tumor progression, highlighting therapeutic potential in targeting histone regulation pathways.

Historical Context

Initial Discovery

The discovery of histones traces back to 1884, when German biochemist isolated a class of basic, acid-soluble proteins from the nuclei of avian erythrocytes, particularly those of goose blood cells, during his investigations into nuclear substances. Kossel noted their abundance and affinity for nucleic acids, distinguishing them from previously identified protamines found in fish sperm, and he coined the term "histone" (from the Greek histos, meaning tissue or web) to describe these nuclear components due to their web-like association with . This isolation was achieved through chemical extraction methods that solubilized the proteins under acidic conditions, highlighting their alkaline (basic) nature rich in and residues. By the 1910s, Kossel's work had formalized the and extraction techniques for histones, including alkaline-based methods to separate them from , as detailed in his lecture where he emphasized their widespread salt-like combination with nucleic acids across animal tissues. These early characterizations established histones as essential components of cell nuclei, though their precise role remained unclear beyond basic binding to DNA. Kossel's contributions, recognized with the 1910 in or , laid the groundwork for understanding nuclear proteins but were limited by the era's biochemical tools. Further confirmation of histones as distinctly basic proteins came in the 1960s with the advent of , which allowed separation and visualization of their fractions based on charge and size, revealing their high content of positively charged . Initially, histones were viewed primarily as structural elements for DNA packaging and chromosome organization, with little recognition of potential dynamic roles, a misconception that persisted until subsequent decades.

Key Experimental Advances

A pivotal experimental advance came in 1964, when Vincent Allfrey and colleagues at used radioactive labeling and enzymatic assays on calf thymus nuclei to demonstrate that histones undergo dynamic post-translational modifications, specifically and at residues, correlating these changes with synthesis rates. This finding suggested that covalent modifications could reversibly regulate by altering accessibility, shifting the view of histones from static scaffolds to dynamic regulators. In 1974, Roger Kornberg proposed a model for chromatin structure in which the basic repeating unit, the nucleosome, consists of approximately 200 base pairs of DNA associated with an octamer of core histones (two each of H2A, H2B, H3, and H4), with linker DNA bound by histone H1. This model was supported by biochemical evidence and prior structural data, explaining DNA packaging into chromosomes and providing a mechanistic basis for how modifications might influence accessibility, confirmed later by Aaron Klug's structural studies. Genetic experiments in the 1980s further elucidated histone functions. In 1988, Michael Grunstein's team at UCLA engineered strains with deletions or mutations in histone H4 genes, showing that reducing H4 levels led to derepression of silent loci near telomeres and rDNA, as measured by assays and , demonstrating histones' role in . The 1990s brought biochemical identification of modification machinery. In 1996, C. David Allis and colleagues purified a (HAT) from thermophila using activity-based fractionation and sequencing, identifying it as homologous to the transcriptional co-activator Gcn5, linking HATs directly to . This was complemented by 2000 discoveries of histone methyltransferases; Thomas Jenuwein and Allis's groups identified SUV39H1 as a site-specific lysine 9 (H3K9) methyltransferase from human and mouse cells, using purification and assays, showing that this modification recruits proteins like HP1 for repression. These advances culminated in the "histone code" hypothesis, proposed by Allis and Jenuwein in based on integrated biochemical and genetic data, positing that combinations of modifications form a code interpreted by chromatin-binding proteins to dictate transcriptional outcomes. Subsequent experiments, such as followed by (ChIP-chip) in the early , validated this by mapping modification patterns genome-wide in and mammals, revealing their roles in diverse processes like development and .

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