histone

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

In biology, histones are the chief protein components of chromatin. They act as spools around which DNA winds, and they play a role in gene regulation. Without histones, the unwound DNA in chromosomes would be very long. For example, each human cell has about 1.8 meters of DNA, but wound on the histones it has about 90 millimeters of chromatin, which, when duplicated and condensed during mitosis, result in about 120 micrometers of chromosomes.^[1]

Classes

PDB rendering of H2AFJ based on 1aoi.
Core histone H2A/H2B/H3/H4
Identifiers
Symbol	Histone
Pfam	PF00125
InterPro	IPR007125
SCOP	1hio
Available PDB structures: 1eqz, 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

PDB rendering of HIST1H1B based on 1ghc.
linker histone H1 and H5 family
Identifiers
Symbol	Linker_histone
Pfam	PF00538
InterPro	IPR005818
SCOP	1hst
Available PDB structures: 1ghc, 1hst, 1uhm, 1uss, 1ust, 1yqa

There are a total of six classes of histones (H1, H2A, H2B, H3, H4, and H5) organized into two super classes as follows:

• core histones – H2A, H2B, H3 and H4
• linker histones – H1 and H5

Two of each of the core histones assemble to form one octameric nucleosome core particle by wrapping 146 base pairs of DNA around the protein spool in 1.65 left-handed super-helical turn.^[2] The linker histone H1 binds the nucleosome and the entry and exit sites of the DNA, thus locking the DNA into place^[3] 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:

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)^[2]. 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-transcriptional modification (see below).

Using an electron paramagnetic resonance spin-labeling technique, English researchers measured the distances between the spools around which eukaryotic cells wind their DNA. They determined the spacings range from 59 to 70 Å.^[4]

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

• Helix-dipoles from alpha-helices 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 links 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 the water solubility of histones.

Histones are subject to post translational modification by enzymes primarily on their N-terminal tails, but also in their globular domains^{[citation needed]}. 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^{[citation needed]}. It also appears that the structure of histones has been evolutionarily conserved, as any deleterious mutations would be severely maladaptive.

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 which 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 H3 can also be modified. Combinations of modifications are thought to constitute a code, the so-called "histone code."^[5][6] Histone modifications act in diverse biological processes such as gene regulation, DNA repair and chromosome condensation (mitosis).^{[citation needed]}

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)

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

For an example of histone modifications in transcription regulation see RNA polymerase control by chromatin structure and table.

Influence on gene expression in mammalian cells

History

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 as merely packing material for nuclear DNA. During the early 1990s, the regulatory functions of histones were discovered.^[11]

Conservation across species

Histones are found in the nuclei of eukaryotic cells, and in certain Archaea, namely Euryarchaea, but not in bacteria. 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.^{[citation needed]} In contrast mature sperm cells largely use protamines to package their genomic DNA, most likely to achieve an even higher packaging ratio.^[12]

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.^{[citation needed]}

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 only associated with 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 formation of the heterochromatin. Another H2A variant H2A.X binds to the DNA with double strand breaks and marks the region undergoing DNA repair. Histone H3.3 is associated with the body of actively transcribed genes.^[13]

See also

• Nucleosome
• Chromatin
• Histone-Modifying Enzymes
• Histone deacetylase
• PRMT4 pathway
• Gene silencing
• Genetics
• Histone methyltransferase
• Histone acetyltransferase

References

External links

• Chromatin, Histones & Cathepsin; PMAP The Proteolysis Map-animation
• Nextbio