What are histones?
Histones are a special group of proteins found in the nuclei of eukaryotic cells responsible for DNA folding and chromatin formation. This is important because without histones DNA would be extremely long in relation to the cell. It also allows for additional gene regulatory control, with the modification of DNA packing controlling access to transcriptional machinery. Eukaryotic chromatin structure consists of repeating units, known as nucleosomes, which resemble beads on a string connected by sequences of linker DNA. A nucleosome is formed of DNA sections (approximately 145-146 bp) wrapped around a core octamer of eight histones.
Types of histones
Each octamer has two pairs of different histone proteins: H2A, H2B, H3 and H4. They are arranged as a pair of H2A-H2B dimers, and an (H3)2(H4)2 tetramer. There is an additional type of histone, the linker histone H1, which is present in condensed DNA. Histone H1 is associated with the linker regions connecting core particles, and is required to obtain condensed 30-nm chromatin fibres from the smaller “beads on a string” fibres of approximately 10-11 nm . Although histone H1 is the most commonly studied linker histone there are others, for example histone H5 is the substitute for H1 in nucleated erythrocytes.
Histone packaging of DNA is a ubiquitous mechanism throughout species, and the structures of histones are highly conserved. They contain high amounts of two positively charged amino acids: lysine and arginine. Of course, there are some differences between the types of histone proteins:
- H2A and H2B contain more lysine;
- H3 and H4 contain more arginine.
- H1 (H5) has the highest lysine/arginine ratio.
The N-terminal and C-terminal ends of the histones have different functions:
- The C-terminal end is primarily responsible for histone-DNA and histone-histone interactions;
- The N-terminal consists of a charged, flexible tail which in histones H2B and H3 bury into the minor grooves of DNA, probably to stabilise the interaction. The H4 tail contains a large proportion of lyseine residues and is thought to be involved in forming higher order chromatin structure by binding to negatively charged regions of other nucleosomes. The tails stand as targets of post-transational modifications, which may modify the structure of chromatin.
Histones vary in their affinity for and interaction with each other:
- High affinity, dimer formation: H2A – H2B; H2B – H4;
- High affinity, tetramer formation: H3 – H4;
- Weaker interaction: H2A – H3;
- Weakest interaction: H2A – H4; H2B –H3.
Histone DNA interactions
Histones contain a large proportion of the positively charged (basic) amino acids, lyseine and arginine in their structure. DNA is negatively charged due to the phosphate groups on its backbone. These result of these opposite charges is strong attraction and therefore high binding affinity between histones and DNA. Hydrogen bonding involving hydroxyl amino acids in the histone peptide and the phosphodiester backbone of DNA and are also important in further stabilizing the structure. One of the advantages of histones interacting mainly with the backbone of DNA is it means the interaction is not sequence dependent. This means that despite an apparent preference of histones to some sequences of DNA, they are able to bind anywhere.
Importance of histone modifications
- Chromatin structure is dependent on the N-terminal tails of the core histones
- These can undergo modifications, which can take place either before or after the nucleosome assembles
- Example of modifications: acetylation/ methylation of lysine, serine phosphorylation or ubiquitination, along with their reversed processes
- These modifications affect the chromatin fiber stability, and are catalyzed by enzymes found in the nucleus, such as HATs (histone acetyl transferases) and HDACs (histone deacetylases)
- One of the most important characteristics of histone tails which suffered modifications is their capacity to attract certain proteins, which may compact the chromatin even further, or facilitate DNA access
- There is a standard nomenclature, also known as the Brno nomenclature, which was adopted to simplify the presentation of histone modifications
- In this nomenclature, the “site” refers to the position of the amino acid in the protein sequence
Examples of important histone modifications
- Lysine methylation can either activate or repress gene expression. Which of these effects it has depends on both the location of the modified lysine and which histone is the target. For example, if this occurs at lysine 4 in histone H3, it is linked to gene activation (Schneider et al, 2004), and if it occurs at lysine 9 it is a marker for gene silencing (Jackson et al, 2004).
- Histone acetylation is linked to epigenetic regulation. Histone acetyletransferase (HAT) complexes are recruited by transcription activator proteins , while the repressor proteins recruit histone deacetylase (HDAC) complexes. These add and remove acetylations respectively. Acetylation removes the negative charge from lysine so it can no longer bind to the DNA phosphate backbone. This weakens the interaction between histones and DNA, resulting in a more relaxed DNA structure which is more available for DNA transcription.
Despite their important role, histones aren’t found in all eukaryotic cells. Dinoflagellates were found to have completely different proteins which act in the same manner, and the spermatozoa makes use of protamines to package most of the DNA.
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