Histones

Histones can be modified by a variety of covalent modifications on their N-terminal amino acid tails by either acetylation, methylation, phosphorylation, ubiquitination symoylation etc.

These can occur at specific amino acid positions and residues and in different combinations and depending on what position and combination, these modifications occur, it can lead to either activation of gene expression or repression of transcription. This is termed the histone code.

Acetylation at specific amino acid residues on the histones generally leads to transcriptional activation. Acetylation is carried out by enzymes called histone acetyl transferases (HATS) and usually on lysine and arginine residues in the Nterminal tail region of the histones. This acetylation causes a decrease affinity of histone core proteins for DNA thus leading to decrease interactions between nucleosomes that form the 30nm fibre and thus relaxing and exposing or destabilising the DNA allowing easy accesss of transcription factors to promoters. This is also observed wherein doubly acetylated histone H4 is read by a set of proteins that lead to activation of transcription. On the other hand, acetyl groups can be removed from the DNA by the action of enzymes called HDACS (histone deactylases) and this causes rather transcriptional repression as seen in the control of X-inactivation by histone modifications whereby there is hypoacetylation of histone H4 on the inactivated X chromosome leading to formation of heterochromatin and bar body production.

On the other hand, methylation usually leads to repression of gene expression. Methylation also occurs on lysine residues and this usually blocks access to the promoter regions on the chromatin structure. For example methylation of hoistone H3 is recognised by an enzyme that provokes development of a compacted form of the chromosome. Again, a modification at one point on the histone tail region may lead to a block in the modification of the same amino acid residue or even at another amino acid residue or position e.g methylation of histone H3 at lys 9 prevents acetylation at that same position and vice versa. An example of the effect of methylation is seen in pericentromeric chromosome which contains highly methylated histone proteins, leading to formation of the compact heterochromatin nature of the centromeres and telomeres.

Phosphorylation usually occurs on the serine residues and according to the histone code, a modification at a specific cite may have different meanings on the nearby chromatin structure. Phosphorylation of histone h3 position 10 leads to condensation of chromatin in that region but rather allows gene expression in certain areas.

The code is also used to distinguish newly sunthesised DNA from template DNA as usually the daughter strands are methylated immediately after replication.

In conclusion, owing to the effect of these covalent histone modifications on the structure and function of chromatin, they thus greatly serve as a means of control of gene expression as observed in the cases of development of hetero and euchromatin.

Conventional histone proteins found in the nucleosome of chromosome include histone H1, h2a, h2b, h3 and h4 . Apart from histone H4 these histone proteins have also been shown to have variants which differ from them in the amino acid composition of the globular N and C terminal domains. However histone and their variants are very essential in providing the three dimensional chromosomal integrity (DNA repair) and function in (terms of replication and transcription) of the dna molecule.

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Histone variants are usually expressed at low levels within the cell and unlike the normal histones are their expression is not restricted to the S phase of the cell cycle but are constitutively expressed throught out the cell cycle. Once expressed also can at any time incorporated themselves into the chromosome through exchange or replacement of pre-existing histones. Together with histone modifications (acetylation, methylation) can allow changes in nucleosme structure and hence regulate structure and functioning of the chromosome either making it more or less accessible for transcription or replication.

Histone variants for histone H1 are numerous and include variants such as H10, H5 which are sperm specific variants. Their abundance fluctuates within the cell during the cell cycle, developmemt and differentiation and have been shown to have a role in the gene repression during differentiation.

Histone H2A has the largest number of variants and examples include H2a. Z,Macro H2A etc. And the variants are distinguisehed by length and sequence of their C terminal tail that diverge greatly in the variants. H2a.Z is one of the most important and has been linked to both transcriptional activation and repression. In transcriptional activation, it has been shown to be involved in the recruitment of transcription complexes to the promoters of some genes thus it causes induction.Thus can be used in vitro for switching on and off genes. H2B has few variants available but has been shown to be linked to specialised roles in chromatin compaction and transcription repression.

H3 Has many variants H3.3 , cenH3 , CENP-A (mammalian specific centromeric protein). Since cetromeric chromatin is mainly heterochromatin, it may have a repressive role in transcription.

H4 has no known sequence variants but however is constitutively expressed throughout the cell cycle.

In conclusion, histone and histone variants have an essential role in the controlling chromosomal behaviour .However a lot still remains unclear about role or functioning of these variants.

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