Structural Biochemistry/Proteins/Histone Modifications

=Histone=

A Histone is an alkaline protein found in eukaryotic cells that orders the DNA stain and plays a role in gene regulation. In order for DNA to form into chromosomes the DNA coils around the histone protein to form chromatin, without this process life would not exist.

Classes
There are five major classes of Histones: H1/H5, H2A, H2B, H3, and H4. Histones H2A, H2B, H3, and H4 are known as the core histones, while histones H1/H5 are known as the linker histones. A nucleosome core particle is a combination of two of each of the core histones, and this core particle is responsible for winding up a section of the DNA, approximately 147 base pairs. The linker histone keeps the wound section of DNA in place by binding to the neucleosome and to the entry and exit sites of the DNA, locking it into place. The combination of DNA wound up in histones is called a chromatin.

Functions of Histone Modifications
Sometimes histone modifications affect the structure of chromatin, or they may act as a mark or a signal for protein effectors.

Alterations of the Structure of Chromatin

High orders of chromitin structure can be directly affected by Histone modifications. Removal of Histone tails by trypsin results in a decrease of the ability of nucleosome arrays to comdense into 30 nanometer chromatin fibers. Acetylation of H4K16 has also been experimentally shown to inhibit the formation of 30-nm chromatin fibers. Many Histone Acetyltransferase (HAT) complexes have the function of acetylating multiple lysines of Histone H4, including H4K16. Histone acetylation occurs at the lysine residues and is recognized by the bromo domain proteins. It is important for chromatin decondensation and euchromatin formation. Euchromatin is considered to be open chromatin and is more accessible to proteins. Thus, acetylation leads to additional transcriptional factors binding and thus the DNA can be available for transcription. Acetylation of H4K16 serves an important part in DNA replication, gene splicing, and life-span regulation of yeast.

Chromatin can also be altered by methylation at the lysines and the arginines by histone methyl transferases (HMT) which add on methyl groups. These are recognized by chromo domain proteins and is important for the condensation of chromatin and heterochromatin formation. Heterochromatin is considered to be tightly closed chromatin and is less accessible to proteins.

Source: Molecular Cell Biology, Lodish et al., 6th edition (2008), pages 247-257

Targeting and/or Activating Chromatin-Remodeling Complexes

Histone modifications can also affect chromatin structures by acting as marks for the activity or the gathering of protein complexes that change and reconstruct the chromatin structure. These are ATP-dependent chromatin remodeling complexes which are a group of proteins that slide nucleosomes on DNA with the purpose of changing or getting rid of the histones. The nucleosome remodeling complexes have one to twelve subunits that include multiple protein domains that interact with DNA. Often, these domains recognize histone modifications. One of the first domains discovered to interact with an already modified histone and to recognize acetyl-lysine residues in the histones were bromodomains. These bromodomains found in subunits of the SWI/SNF family of chromatin-remodeling complexes play an important role in gene activation. For example, acetylated histones can be evicted from the DNA complex and replaced with the SWI/SNF complex (Figure 1). This process occurs when sequence-specific DNA-binding transcription activators recruit the SAGA histone acetyltransferase to target the genes where SAGA acetylated a patch of nucleosomes on the promoter region. Then, the same activators can obtain the SWI/SNF nucleosome -remodeling complex to the same site and binds to the acetylated histones. Finally, the SWI/SNF complex uses the energy of ATP hydrolysis to displace the acetylated histones generating a neucleosome free region.

Actively Transcribed Genes

Two of the histone modifications are involved in active transcription

-Trimethylation of H3 lysine 4 at the promoter of active genes, which is done by the COMPASS complex. The role of this modification is not clear, but the level of this modification is correlated with the transcriptional activity of the gene.

-Trimethylation of H3 lysine 36 at the body of active genes. This modification is recognized by the Rpd3 histone, which deacetylates surrounding histones. This increases chromatin compaction, which prevents the likelihood of new transcription events from occurring while one is already in progress. This helps to ensure that a transcription in progress is not interrupted.

Repressed Genes

There are three histone modifications that are associated with gene repression.

-Trimethylation of H3 lysine 27. This is done by the polycomb complex PRC2, which is usually bound with other proteins and it binds to the gene, causing chromatin compaction, which silences transcription activity. PRC1 has also been known to aid PRC2 in the histone modification.

-Di and trimethylation of H3 lysine 9 is a well-known marker for heterochromatin, a tightly packed form of DNA. An RNA-induced transcriptional silencing complex (RITS) is responsible for this modification.

-Trimethylation of H4 lysine 20 is a modification done by Suv4-20hmethyltransferase that is also associated with heterochromatin.