HISTONE VARIANTS: SPICE IN CHROMATIN

Name : Keshav Jha

Roll No.: 20151111(3rd Year BSMS)

The eukaryotic genome being very big in size, has to be compacted by various
folds so as to fit into the nucleus which is hardly few micrometers in diameter.
This high level of compactness is achieved by wrapping the DNA on the
histone proteins forming nucleosome that folds further to wind all the DNA
inside the tiny nucleus.
In Hindu mythology, the positive energy God is said to be one but existing in
diverse forms so as to handle different issues. Akin to the Paramatman, is the
positively charged histones that confer different states to the chromatin in
order to encode and inherit the epigenetic changes.

Histones have been evolving with time. Higher organisms seem to have more
diverse variety in histones . Histone variants like CENP-A and H3.3 are
present in all eukaryotes. Other variants like H2AZ, H2AX, H2ABbd,
macroH2A are also found in different eukaryotes based on their complexity.
Few variants are also specific to primates only like H3.X, H3.Y and many
variants of H1 variants.

The canonical histones, by default, compacts the DNA locally and keeps the
trans-acting factors like the transcription factors and RNA POLIII from
accessing the DNA. The histone variant H3.3 and H2A.Z are chiefly involved in
the regulation of transcription. In various studies, it has been shown that in vivo,
the stability of the H3.3/H2A.X nucleosomes is much less than the canonical
histone nucleosomes. Even the small alteration in the salt concentration can
result in the dislodging of the variant histones from the nucleosome leaving
behind the Nucleosome Deficient Regions (NDR). These NDRs are usually the
promoter sites for genes from where the transcription can be initiated.
On the other hand, certain histone variants confer extra compaction to the
genome locally, chiefly to silent certain genes temporarily or permanently. For
instance, CENP-A nucleosome imparts a high degree of compaction at the
centromeric region of the chromosome which is chiefly occupied by the
noncoding genes and repetitive sequences. Similarly, macro H2A is
involved in the X chromosome inactivation in human females.

The histone variants store very specific epigenetic information about the
genome locally.Their inheritance is important for maintaining the state of the
chromatin. With the SILAC (Stable Isotope Labelling by amino acids in Cell
culture) technique, it was estimated that 20percent of the H3.3/H4 nucleosome
are inherited in the semi-conserved fashion i.e. replication-dependent. With
the unwinding of the DNA, the H3.3/H4 tetramer spits into dimers
and get equally distributed onto the two new strands. Then using the protein
complexes like CAF1, newly synthesised H3.3 dimers are inserted with the
old dimers on both the strands.

Rest of the H3.3/H4 nucleosomes get inherited in the conserved way i.e. the
epigenetic state is recovered after the replication using the
neighbouring strand as the template. Here CAF1 brings two new H3.3/H4
dimers for the formation of one octamer.
It is known for quite some time that the naked DNA are susceptible for
double strand break(DSBs) more than the chromatinsed ones, on
exposure to the high-frequency radiation. But the role of specific histone
variants in this has been recently figured out. H2A variants like (γ)H2A.X,
H2A.Z and macroH2A are mostly involved in this.

Upon the damage, the kinases like ATM and DNA-pk, phosphorylates the
H2A.X tail. This is followed by the insertion of H2A.Z in the nucleosome at the
site of the lesion by the ATP dependent chromatin remodelling complex p400.
This leads to further acetylation of the H4 and chromatin entering into the more
fluid state. Upon this, the usual DNA repair machinery sits and repair the
breaks. The role of the macro H2A variant is presently unclear. This way, the
histones variants play a crucial role in the repair of DNA during the
double-strand breaks.
In the studies on S cerevisiae, the role of histones in the aging has been
revealed. The overexpression of histones and artificial inactivation of Hir
chaperones can extend the life of the organism.
Most cancers have some or the another link with the histones and its variants.
The pervasiveness of cancer cell lines has nee found to be related to the
amount of H2A histone variant. Higher the amount of macroH2A1.2
than macroH2A1.1, more ivasive is the cell and viceversa. The real pathway
through this happens still unknown like most other issues in this field. It may be
due to the change in the downstream genes that these histones are guarding
to. Untrestable diseases like pediatric gliomas are also found to be caused
due to the mutations in the tail of the histone variants (K27M mutation on H3.3
tail leading to gain of function). These make the study of histone variants
inevitable for the Erly detection of the disease. patient stratification, therapeutic
targetting and testing the drug efficacy.

Over the last two decades, the understanding of the histone variants and its
role in the transcription regulation, DNA damage repair, pharmaco-epigenetics
and many other biological aspects have improved. Now our perception
towards any of the mentioned topics has escaped the realms of genetic
studies and wonders in the ingredients of epigenetics with the spices being the
histone variants undoubtedly which will hopefully cook up our complete
understanding of the genes some day.