M E D I C I N E:
 Epigenetics, Nucleosome Structure, and Histone Variants

Information that is passed from one generation to the
next— to daughter cells at cell division or from parent to
offspring—but is not encoded in DNA sequences is referred
to as epigenetic information. Much of it is in the
form of covalent modification of histones and/or the
placement of histone variants in chromosomes.
The chromatin regions where active gene expression
(transcription) is occurring tend to be partially
decondensed and are called euchromatin. In these regions,
histones H3 and H2A are often replaced by the

histone variants H3.3 and H2AZ, respectively.
Shown here are the core histones and a few of the known variants.
Sites of Lys /Arg residue methylation and Ser phosphorylation are indicated.
HFD denotes the histone-fold domain, a structural domain
common to all core histones chaperones, helping to ensure the proper assembly
and placement of nucleosomes. Histone H3.3
differs in sequence from H3 by only four amino acid
residues, but these residues all play key roles in histone
Like histone H3.3, H2AZ is associated with a distinct
nucleosome deposition complex, and it is generally
associated with chromatin regions involved in
active transcription. Incorporation of H2AZ stabilizes
the nucleosome octamer, but impedes some cooperative
interactions between nucleosomes that are needed
to compact the chromosome. This leads to a more open
chromosome structure that facilitates the expression
of genes in the region where H2AZ is located. The
gene encoding H2AZ is essential in mammals. In fruit
flies, loss of H2AZ prevents development beyond the larval stages.
Another H2A variant is H2AX, which is associated
with DNA repair and genetic recombination. In mice,
the absence of H2AX results in genome instability and
male infertility. Modest amounts of H2AX seem to be
scattered throughout the genome. When a double strand
break occurs, nearby molecules of H2AX become

phosphorylated at Ser139 in the carboxyl-terminal region. If this phosphorylation is blocked experimentally,
formation of the protein complexes necessary for DNA
repair is inhibited.
The H3 histone variant known as CENPA is associated
with the repeated DNA sequences in centromeres.
The chromatin in the centromere region contains the histone
chaperones CAF1 and HIRA, and both proteins
could be involved in the deposition of nucleosomes containing
CENPA. Elimination of the gene for CENPA is
lethal in mice.
The function and positioning of the histone variants
can be studied by an application of technologies used in
genomics. One useful technology is chromatin immunoprecipitation,
or chromatin IP (ChIP). Nucleosomes
containing a particular histone variant are precipitated
by an antibody that binds specifically to this variant. 

Please visit these links :
environmental-medicine.med.nyu.edu › Research Divisions › Our Labs
www.ncbi.nlm.nih.gov › Journal List › NIHPA Author Manuscripts


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