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The core histones all exist as [[Protein dimer|dimer]]s, 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).<ref>{{cite journal | vauthors = Mariño-Ramírez L, Kann MG, Shoemaker BA, Landsman D | title = Histone structure and nucleosome stability | journal = Expert Review of Proteomics | volume = 2 | issue = 5 | pages = 719–29 | date = Oct 2005 | pmid = 16209651 | pmc = 1831843 | doi = 10.1586/14789450.2.5.719 }}</ref> 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.<ref name=pmid9305837>{{cite journal | vauthors = Luger K, Mäder AW, Richmond RK, Sargent DF, Richmond TJ | title = Crystal structure of the nucleosome core particle at 2.8 A resolution | journal = Nature | volume = 389 | issue = 6648 | pages = 251–60 | date = Sep 1997 | pmid = 9305837 | doi = 10.1038/38444 }} {{PDB|1AOI}}</ref> The linker histone H1 binds the nucleosome at the entry and exit sites of the DNA, thus locking the DNA into place<ref name="isbn0-915274-84-1">{{cite book | last = Farkas | first = Daniel |title=DNA simplified: the hitchhiker's guide to DNA |publisher=AACC Press |location=Washington, D.C |year=1996 |isbn=0-915274-84-1 | name-list-format = vanc }}</ref> and allowing the formation of higher order structure. The most basic such formation is the 10&nbsp;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 [[nucleosome]]s (also referred to as linker [[DNA]]). Higher-order structures include the 30&nbsp;nm fiber (forming an irregular zigzag) and 100&nbsp;nm fiber, these being the structures found in normal cells. During mitosis and meiosis, the condensed [[chromosome]]s are assembled through interactions between nucleosomes and other regulatory proteins.
The core histones all exist as [[Protein dimer|dimer]]s, 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).<ref>{{cite journal | vauthors = Mariño-Ramírez L, Kann MG, Shoemaker BA, Landsman D | title = Histone structure and nucleosome stability | journal = Expert Review of Proteomics | volume = 2 | issue = 5 | pages = 719–29 | date = Oct 2005 | pmid = 16209651 | pmc = 1831843 | doi = 10.1586/14789450.2.5.719 }}</ref> 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.<ref name=pmid9305837>{{cite journal | vauthors = Luger K, Mäder AW, Richmond RK, Sargent DF, Richmond TJ | title = Crystal structure of the nucleosome core particle at 2.8 A resolution | journal = Nature | volume = 389 | issue = 6648 | pages = 251–60 | date = Sep 1997 | pmid = 9305837 | doi = 10.1038/38444 }} {{PDB|1AOI}}</ref> The linker histone H1 binds the nucleosome at the entry and exit sites of the DNA, thus locking the DNA into place<ref name="isbn0-915274-84-1">{{cite book | last = Farkas | first = Daniel |title=DNA simplified: the hitchhiker's guide to DNA |publisher=AACC Press |location=Washington, D.C |year=1996 |isbn=0-915274-84-1 | name-list-format = vanc }}</ref> and allowing the formation of higher order structure. The most basic such formation is the 10&nbsp;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 [[nucleosome]]s (also referred to as linker [[DNA]]). Higher-order structures include the 30&nbsp;nm fiber (forming an irregular zigzag) and 100&nbsp;nm fiber, these being the structures found in normal cells. During mitosis and meiosis, the condensed [[chromosome]]s are assembled through interactions between nucleosomes and other regulatory proteins.


Histones are subdivided into canonical replication-dependent histones that are expressed during the S-phase of cell cycle and replication-independent [[histone variants]], expressed during the whole cell cycle. In animals, genes encoding canonical histones are typically clustered along the chromosome, 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. Complex multicellular organisms typically have a higher number of histone variants providing a variety of different functions. Recent data are accumulating about the roles of diverse histone variants highlighting the functional links between variants and the delicate regulation of organism development. Histone variants from different organisms, their classification and variant specific features can be found in [https://www.ncbi.nlm.nih.gov/projects/HistoneDB2.0/ "HistoneDB 2.0 - Variants"] database.
Histones are subdivided into canonical replication-dependent histones that are expressed during the S-phase of cell cycle and replication-independent [[histone variants]], expressed during the whole cell cycle. In animals, genes encoding canonical histones are typically clustered along the chromosome, 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. Complex multicellular organisms typically have a higher number of histone variants providing a variety of different functions. Recent data are accumulating about the roles of diverse [[histone variants]] highlighting the functional links between variants and the delicate regulation of organism development. [[Histone variants]] from different organisms, their classification and variant specific features can be found in [https://www.ncbi.nlm.nih.gov/projects/HistoneDB2.0/ "HistoneDB 2.0 - Variants"] database.


The following is a list of human histone proteins:
The following is a list of human histone proteins:

Revision as of 20:29, 1 February 2017

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

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 playing 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 1 in human DNA). For example, each human diploid cell (containing 23 pairs of chromosomes) 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]

Core histone H2A/H2B/H3/H4
PDB rendering of Complex between nucleosome core particle (h3,h4,h2a,h2b) and 146 bp long DNA fragment based on 1aoi.
Identifiers
SymbolHistone
PfamPF00125
Pfam clanCL0012
InterProIPR007125
SCOP21hio / SCOPe / SUPFAM
Available protein structures:
Pfam  structures / ECOD  
PDBRCSB PDB; PDBe; PDBj
PDBsumstructure summary
PDB1eqz​, 1f66​, 1hq3​, 1id3​, 1kx3​, 1kx4​, 1kx5​, 1m18​, 1m19​, 1m1a​, 1p34​, 1p3a​, 1p3b​, 1p3f​, 1p3g​, 1p3i​, 1p3k​, 1p3l​, 1p3m​, 1p3o​, 1p3p​, 1q9c​, 1s32​, 1tyz​, 1u35​, 2aro​, 2cv5​, 2hio​
linker histone H1 and H5 family
PDB rendering of HIST1H1B based on 1ghc.
Identifiers
SymbolLinker_histone
PfamPF00538
InterProIPR005818
SMARTSM00526
SCOP21hst / SCOPe / SUPFAM
Available protein structures:
Pfam  structures / ECOD  
PDBRCSB PDB; PDBe; PDBj
PDBsumstructure summary
PDB1ghc​, 1hst​, 1uhm​, 1uss​, 1ust​, 1yqa​

Classes and histone variants

Five major families of histones exist: H1/H5, H2A, H2B, H3, and H4.[2][4][5][6] Histones H2A, H2B, H3 and H4 are known as the core 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 that are expressed during the S-phase of cell cycle and replication-independent histone variants, expressed during the whole cell cycle. In animals, genes encoding canonical histones are typically clustered along the chromosome, 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. Complex multicellular organisms typically have a higher number of histone variants providing a variety of different functions. Recent data are accumulating about the roles of diverse histone variants highlighting the functional links between variants and the delicate regulation of organism development. Histone variants from different organisms, their classification and variant specific features can be found in "HistoneDB 2.0 - Variants" database.

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, 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

Structure

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 (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.[10]

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.[11]

In all, histones make five types of interactions with 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
  • Salt bridges and hydrogen bonds between side chains of basic amino acids (especially lysine and arginine) and phosphate oxygens 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.[12][13] 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[citation needed]. 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.

History

Histones were discovered in 1884 by Albrecht Kossel. The word "histone" dates from the late 19th century and is from the German word "Histon", a word itself of uncertain origin - perhaps from the Greek histanai or histos. 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[14] showed that a nucleosome on a core promoter prevents the initiation of transcription in vitro, and Michael Grunstein[15] 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 earlier proposed a role of histone modification in transcriptional activation,[16] regarded as a molecular manifestation of epigenetics. Michael Grunstein[17] and David Allis[18] 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,[19] and it is now considered an isoform of Histone H1.[2][4][5][6]

Conservation across species

Histones are found in the nuclei of eukaryotic cells, and in certain Archaea, namely Thermoproteales and Euryarchaea, but not in bacteria. The unicellular algae known as dinoflagellates were previously thought to be the only eukaryotes that completely lack histones,[20] however, later studies showed that their DNA still encodes histone genes.[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.

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.[23] Furthermore, H2A.Z has roles in chromatin for genome stability.[24] Another H2A variant H2A.X is phosphorylated at S139 in regions around double-strand breaks and marks the region undergoing DNA repair.[25] Histone H3.3 is associated with the body of actively transcribed genes.[26]

Function

Compacting DNA strands

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.

Chromatin regulation

Histones undergo posttranslational modifications that alter their interaction with DNA and nuclear proteins. The H3 and H4 histones have long tails protruding from the nucleosome, which can be 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 are thought to constitute a code, the so-called "histone code".[27][28] Histone modifications act in diverse biological processes such as gene regulation, DNA repair, chromosome condensation (mitosis) and spermatogenesis (meiosis).[29]

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 transcription regulation include:

Type of
modification 		Histone
H3K4 H3K9 H3K14 H3K27 H3K79 H3K36 H4K20 H2BK5 H2BK20
mono-methylation activation[30] activation[31] activation[31] activation[31][32] activation[31] activation[31]
di-methylation repression[33] repression[33] activation[32]
tri-methylation activation[34] repression[31] repression[31] activation,[32]
repression[31] 		activation repression[33]
acetylation activation[34] activation[34] activation[35] activation

Functions of histone modifications

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

Lysine methylation

The addition of one, two or three 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.

Arginine methylation

What was said above of the chemistry of lysine methylation also applies to arginine methylation, and some protein domains—e.g., Tudor domains—can be specific for methyl arginine instead of methyl lysine. Arginine is known to be mono- or di-methylated, and methylation can be symmetric or asymmetric, potentially with different meanings.

Arginine citrullination

Enzymes called peptidylarginine deiminases (PADs) hydrolyze the imine group of arginines and attach a keto group, so that there is one less positive charge on the amino acid residue. This process has been involved in the activation of gene expression by making the modified histones less tightly bound to DNA and thus making the chromatin more accessible.[36] 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.[37]

Lysine acetylation

Addition of an acetyl group has a major chemical effect on lysine as it neutralises the positive charge. This reduces electrostatic attraction between the histone and the negatively charged DNA backbone, loosening the chromatin structure; highly acetylated histones form more accessible chromatin and tend to be associated with active transcription. Lysine acetylation appears to be less precise in meaning than methylation, in that histone acetyltransferases tend to act on more than one lysine; presumably this reflects the need to alter multiple lysines to have a significant effect on chromatin structure. The modification includes H3K27ac.

Serine/threonine/tyrosine phosphorylation

Addition of a negatively charged phosphate group can lead to major changes in protein structure, leading to the well-characterised role of phosphorylation in controlling protein function. It is not clear what structural implications histone phosphorylation has, but histone phosphorylation has clear functions as a post-translational modification, and binding domains such as BRCT have been characterised.

Functions in transcription

Most well-studied histone modifications are involved in control of transcription.

Actively transcribed genes

Two histone modifications are particularly associated with active transcription:

Trimethylation of H3 lysine 4 (H3K4Me3)
This trimethylation occurs at the promoter of active genes[38][39][40] and is performed by the COMPASS complex.[41][42][43] 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,[44][45] which in turn adds a ubiquitin mark to H2B K123 (K120 in mammals).[46] H2BK123Ub occurs throughout transcribed regions, but this mark is required for COMPASS to trimethylate H3K4 at promoters.[47][48]
Trimethylation of H3 lysine 36 (H3K36Me3)
This trimethylation occurs in the body of active genes and is deposited by the methyltransferase Set2.[49] This protein associates with elongating RNA polymerase II, and H3K36Me3 is indicative of actively transcribed genes.[50] H3K36Me3 is recognised by the Rpd3 histone deacetylase complex, which removes acetyl modifications from surrounding histones, increasing chromatin compaction and repressing spurious transcription.[51][52][53] 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

Three histone modifications are particularly associated with repressed genes:

Trimethylation of H3 lysine 27 (H3K27me3)
This histone modification is depositied by the polycomb complex PRC2.[54] It is a clear marker of gene repression,[55] and is likely bound by other proteins to exert a repressive function. Another polycomb complex, PRC1, can bind H3K27me3[55] and adds the histone modification H2AK119Ub which aids chromatin compaction.[56][57] 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.[58][59]
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 complex to double stranded RNAs produced from centromeric repeats.[60] RITS recruits the Clr4 histone methyltransferase which deposits H3K9me2/3.[61] 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)[62][63] which in turn recruits further repressive activities including histone modifiers such as histone deacetylases and histone methyltransferases.
Trimethylation of H4 lysine 20 (H4K20me3)
This modification is tightly associated with heterochromatin,[64][65] 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.[64]

Bivalent promoters

Analysis of histone modifications in embryonic stem cells (and other stem cells) revealed many gene promoters carrying both H3K4Me3 and H3K27Me3, in other words these promoters display both activating and repressing marks simultaneously. This peculiar combination of modifications marks genes that are poised for transcription; they are not required in stem cells, but are rapidly required after differentiation into some lineages. Once the cell starts to differentiate, these bivalent promoters are resolved to either active or repressive states depending on the chosen lineage.[66]

Other functions

DNA damage

Marking sites of DNA damage is an important function for histone modifications. It also protects DNA from getting destroyed by ultraviolet radiation of sun.

Phosphorylation of H2AX at serine 139 (γH2AX)
Phosphorylated H2AX (also known as gamma H2AX) is a marker for DNA double strand breaks,[67] and forms part of the response to DNA damage.[25][68] H2AX is phosphorylated early after detection of DNA double strand break, and forms a domain extending many kilobases either side of the damage.[67][69][70] Gamma H2AX acts as a binding site for the protein MDC1, which in turn recruits key DNA repair proteins[71] (this complex topic is well reviewed in[72]) 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.[73][74] H3K56 is acetylated by the p300/Rtt109 complex,[75][76][77] but is rapidly deacetylated around sites of DNA damage. H3K56 acetylation is also required to stabilise stalled replication forks, preventing dangerous replication fork collapses.[78][79] 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.[80]

Chromosome condensation

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.[81][82] 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.[83]
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.[84][85] 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.

See also

References

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  2. ^ a b c d Cox, Michael; Nelson, David R.; Lehninger, Albert L (2005). Lehninger Principles of Biochemistry. San Francisco: W.H. Freeman. ISBN 0-7167-4339-6. {{cite book}}: Unknown parameter |name-list-format= ignored (|name-list-style= suggested) (help)
  3. ^ Redon C, Pilch D, Rogakou E, Sedelnikova O, Newrock K, Bonner W (Apr 2002). "Histone H2A variants H2AX and H2AZ". Current Opinion in Genetics & Development. 12 (2): 162–9. doi:10.1016/S0959-437X(02)00282-4. PMID 11893489.
  4. ^ a b "Histone Variants Database 2.0". National Center for Biotechnology Information. Retrieved 13 January 2017.
  5. ^ a b Bhasin M, Reinherz EL, Reche PA (2006). "Recognition and classification of histones using support vector machine". Journal of Computational Biology. 13 (1): 102–12. doi:10.1089/cmb.2006.13.102. PMID 16472024.
  6. ^ a b Hartl, Daniel L.; Freifelder, David; Snyder, Leon A. (1988). Basic Genetics. Boston: Jones and Bartlett Publishers. ISBN 0-86720-090-1. {{cite book}}: Unknown parameter |name-list-format= ignored (|name-list-style= suggested) (help)
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