Modifications of Histones

 

Modifications of Histones:

DNA does not exist naked in the nucleus of the eukaryotic cell but is associatedwith histone proteins in the form of chromatin. The DNA is wrapped aroundthe histone octamer, which consists of two copies each of H2A, H2B, H3 andH4. This protein–DNA complex is called the nucleosome, the smallest unit ofchromatin.Histone H1 is believed to link the nucleosomes together, facilitatingthe formation of higher-order structures of chromatin. Their main functions are to compact DNA and regulate chromatin, therefore impacting gene regulation. Histones H2A, H2B, H3 and H4 are known as the core histones, and they come together to form one nucleosome.The nucleosome core is actually formed of two H2A-H2B dimers and a H3-H4 tetramer. In general, eukaryotic histones repress gene transcription, but It is now known that histones can be both positive and negative regulators of gene expression. These interactions are the basis of the histone code.

Histone Variants and Modifications

1. Histone H2A:Histone H2A is the unique histone that extends both its N- and its C-terminal ends into the extranucleosomal space. Both ends are necessary for telomere position effect on transcription (TPE, or telomeric silencing), as the deletion of either end caused a significant reduction in TPE. N-terminal point mutation of K4R/K7R reduced telomeric silencing as well, whereas K4M/K7M, which mimics the acetylated state, enhanced the TPE phenotype.H2A.Z, a variant of H2A, acted synergistically with boundary elements, preventing the spread of heterochromatin and antagonizing telomeric silencing.

                           There are five possible ubiquitinated residues in H2A (K4, K119,K120,K123 and K126); however, their function remains unclear. Recent work with ubiquitinated H2A indicated that this histone modification did not affect the nucleosome nor the chromatin structure. This suggested that the modification itself could function as a marker for transcription factors interacting with histones. In Tetrahymena, H2A.Z is essential for cell survival. Lysines 4, 7, 10, 13, 16 and 21 are the only acetylated residues in H2A.Z. Mutation of these six lysines to arginine is lethal. Retention of one acetylated lysine is sufficient to provide the essential function of H2A.Z.

 

2.Histone H2B: H2B usually forms (H2A-H2B)₂ tetramer. This tetramer and it’s component dimers are easily exchanged in and out of the nucleosome compared to H3 and H4, meaning that the modifications on H2A and H2B are less likely to be maintained in chromatin. H2B-K123 is a conserved ubiquitination site. Its mutation is shown to confer defects in mitotic cell growth and meiosis.Preubiquitination of H2B-K123 results Methylation of H3K4 (lysine 4 of histone H3).

 

3.Histone H3: Histone H3 is one of the core histones. Its post-translational modification is important for the regulation of transcription and chromatin condensation Histone H3 methylation can have a positive (H3-K4 or H3-R17) or negative (H3-K9) influence on transcription. The methylation status of a specific residue can affect the status of other residues, including those on neighbouring histones. Different methylation patterns are thought to cause different biological consequences, which is referred to as the ‘histone code’.

(a) Histone H3K4: Whether  H3 is methylated or acetylated, this site will turn genes fasters.

(b) Histone H3K9: H3K9 does double duty. It can turn genes on by getting acetylated, but can silence them just as easily when methylated. H3K9ac is a particularly important acetylation: it is highly correlated with active promoters. H3K9ac also has a high co-occurrence with H3K14ac and H3K4me3 which together are these three marks are the hallmark of active gene promoters

(c)Histone H3K27:H3K27 is known for one thing:shutting down transcription. When H3K27 is trimethylated, it is tightly associated with inactive gene promoters. It acts in opposition to H3K4me3. Because of its dramatic and predictable effect on gene expression, H3K27me3 is a favorite of epigenesists looking for inactive genes.

(d)Histone H3K36: H3K36 is like a fine wine: complex, intriguing, and an active source of interest among researchers. The modifications occurring at H3K36 are very diverse and don’t share much similarity with each other. They have roles in many important biological processes.

4. Histone H4: Acetylation and deacetylation are dynamic processes, which are executed by specific histone acetyltransferases (HATs) and histone deacetylases. Acetylation is often connected to active gene loci, while deacetylation is linked to repression. Some of the variants of H4 are as follows

 

(a)Histone H4K5: H4K5 is the closest lysine residue to the N-terminal tail of histone H4. Histone H4 forms a strong tetramer with histone H3. Like histone H3, H4 has a long N-terminal tail that is subject to various acetylations and methylations that are associated with many cellular processes. H4 modifications are not as well characterized as H3. H4 has much less sequence variation than the other histones across species; it seem to be structurally restrained by evolution likely due to important function

(b)Histone H4K8:H4K8 is another lysine on that tail of histone H4 that doesn’t get a lot of attention. Like the others in this group, it is only known to be acetylated, it has not been shown to be methylated as of yet. This group of lysines are known to act as transcriptional activators. These lysines are also an excellent example of the histone code hypothesis in action.

(c)Histone H4K12:H4K12 is yet another lysine on the N-terminal tail of histone H4 that yet again is acetylated and not methylated. Starting to sound familiar? Like H4K8ac,H4K12ac is part of a “backbone” of histone modifications that are associated with active promoters. H4K12ac is localized to the promoter, like other H4 acetylations; however, H4 localizes more to gene bodies than the other acetylations. This suggests that H4K8ac serves to facilitate transcriptional elongation.

(d)Histone H4K16: H4K16 is part what should now be a familiar group of lysines on the N-terminal tail of histone H4.H4K16ac has some unique and interesting properties. Though H4K16ac is associated with transcriptional activation, it can also be linked with repression. The bromodomain of TIP5, part of NoRC, binds to H4K16ac. After binding, the NoRC complex serves to silence rDNA by recruiting HATs and DNMTs. Histone H4K20 H4K20 if definitely the odd lysine out on the tail of H4. All the other lysines up until this point are acetylated and not methylated. H4K20 likes to go against the grain and is methylated but not acetylated. Like all lysine residues, H4K20 can be mono, di, or tri methylated. In the case of H4K20, these methylation states have different spatial disruptions and functions.