In biology, histones are highly alkaline proteins found in eukaryotic cell nuclei that package and order the DNA into structural units called nucleosomes.[1][2] They are the chief protein components of chromatin, acting as spools around which DNA winds, and play a role in gene regulation. Without histones, the unwound DNA in chromosomes would be very long (a length to width ratio of more than 10 million to one in human DNA). For example, each human cell has about 1.8 meters of DNA, but wound on the histones it has about 90 micrometers (0.09 mm) of chromatin, which, when duplicated and condensed during mitosis, result in about 120 micrometers of chromosomes.[3]
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| Core histone H2A/H2B/H3/H4 | |||||||||
|---|---|---|---|---|---|---|---|---|---|
| PDB rendering of H2AFJ based on 1aoi. | |||||||||
| Identifiers | |||||||||
| Symbol | Histone | ||||||||
| Pfam | PF00125 | ||||||||
| Pfam clan | CL0012 | ||||||||
| InterPro | IPR007125 | ||||||||
| SCOP | 1hio | ||||||||
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| linker histone H1 and H5 family | |||||||||
|---|---|---|---|---|---|---|---|---|---|
| PDB rendering of HIST1H1B based on 1ghc. | |||||||||
| Identifiers | |||||||||
| Symbol | Linker_histone | ||||||||
| Pfam | PF00538 | ||||||||
| InterPro | IPR005818 | ||||||||
| SMART | SM00526 | ||||||||
| SCOP | 1hst | ||||||||
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Five major families of histones exist: H1/H5, H2A, H2B, H3, and H4.[2][4][5] Histones H2A, H2B, H3 and H4 are known as the core histones, while histones H1 and H5 are known as the linker histones.
Two of each of the core histones assemble to form one octameric nucleosome core particle, and 147 base pairs of DNA wrap around this core particle 1.65 times in a left-handed super-helical turn.[6] The linker histone H1 binds the nucleosome and the entry and exit sites of the DNA, thus locking the DNA into place[7] 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). The assembled histones and DNA is called chromatin. 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.
The following is a list of human histone proteins:
| Super family | Family | Subfamily | Members |
|---|---|---|---|
| Linker | |||
| H1 | |||
| H1F | H1F0, H1FNT, H1FOO, H1FX | ||
| H1H1 | HIST1H1A, HIST1H1B, HIST1H1C, HIST1H1D, HIST1H1E, HIST1H1T | ||
| Core | |||
| H2A | |||
| H2AF | H2AFB1, H2AFB2, H2AFB3, H2AFJ, H2AFV, H2AFX, H2AFY, H2AFY2, H2AFZ | ||
| H2A1 | HIST1H2AA, HIST1H2AB, HIST1H2AC, HIST1H2AD, HIST1H2AE, HIST1H2AG, HIST1H2AI, HIST1H2AJ, HIST1H2AK, HIST1H2AL, HIST1H2AM | ||
| H2A2 | HIST2H2AA3, HIST2H2AC | ||
| H2B | |||
| H2BF | H2BFM, H2BFO, H2BFS, H2BFWT | ||
| H2B1 | HIST1H2BA, HIST1H2BB, HIST1H2BC, HIST1H2BD, HIST1H2BE, HIST1H2BF, HIST1H2BG, HIST1H2BH, HIST1H2BI, HIST1H2BJ, HIST1H2BK, HIST1H2BL, HIST1H2BM, HIST1H2BN, HIST1H2BO | ||
| H2B2 | HIST2H2BE | ||
| H3 | |||
| H3A1 | HIST1H3A, HIST1H3B, HIST1H3C, HIST1H3D, HIST1H3E, HIST1H3F, HIST1H3G, HIST1H3H, HIST1H3I, HIST1H3J | ||
| H3A2 | HIST2H3C | ||
| H3A3 | HIST3H3 | ||
| H4 | |||
| H41 | HIST1H4A, HIST1H4B, HIST1H4C, HIST1H4D, HIST1H4E, HIST1H4F, HIST1H4G, HIST1H4H, HIST1H4I, HIST1H4J, HIST1H4K, HIST1H4L | ||
| H44 | HIST4H4 |
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).[6] 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 (which allows the easy dimerisation). 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).
It has been proposed that 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.[8]
Using an electron paramagnetic resonance spin-labeling technique, British researchers measured the distances between the spools around which eukaryotic cells wind their DNA. They determined the spacings range from 59 to 70 Å.[9]
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, SUMOylation, ubiquitination, and ADP-ribosylation. This affects their function of gene regulation (see functions).
In general, genes that are active have less bound histone, while inactive genes are highly associated with histones during interphase. 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.
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.
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, H2B, and H3 can also be modified. Combinations of modifications are thought to constitute a code, the so-called "histone code".[10][11] Histone modifications act in diverse biological processes such as gene regulation, DNA repair, chromosome condensation (mitosis) and spermatogenesis (meiosis).[12]
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.
Examples of histone modifications in transcription regulation include:
| Type of modification |
Histone | ||||||
|---|---|---|---|---|---|---|---|
| H3K4 | H3K9 | H3K14 | H3K27 | H3K79 | H4K20 | H2BK5 | |
| mono-methylation | activation[13] | activation[14] | activation[14] | activation[14][15] | activation[14] | activation[14] | |
| di-methylation | repression[16] | repression[16] | activation[15] | ||||
| tri-methylation | activation[17] | repression[14] | repression[14] | activation,[15] repression[14] |
repression[16] | ||
| acetylation | activation[17] | activation[17] | |||||
Histones were discovered in 1884 by Albrecht Kossel. The word "histone" dates from the late 19th century and is from the German "Histon", of uncertain origin: perhaps from Greek histanai or from histos. Until the early 1990s, histones were dismissed by most as inert packing material for eukaryotic nuclear DNA, based in part on the "ball and stick" 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, work by Michael Grunstein [18] demonstrated that eukaryotic histones repress gene transcription, and that the function of transcriptional activators is to overcome this repression. It is now known that histones play both positive and negative roles in gene expression, forming the basis of the histone code.
The discovery of the H5 histone appears to date back to 1970s,[19][20] and in classification it has been grouped with H1.[2][4][5]
Histones are found in the nuclei of eukaryotic cells, and in certain Archaea, namely Euryarchaea, but not in bacteria. The unicellular algae known as dinoflagellates are the only eukaryotes that completely lack histones.[21]
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.[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.[22]
Core histones are highly conserved proteins; that is, there are very few differences among the amino acid sequences of the histone proteins of different species. Linker histone usually has more than one form within a species and is also less conserved than the core histones.
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 a histone 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 [23]. Furthermore, H2A.Z has roles in chromatin for genome stability [24]. Another H2A variant H2A.X binds to the DNA with double-strand breaks and marks the region undergoing DNA repair.[25] Histone H3.3 is associated with the body of actively transcribed genes.[26]
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