418
Cell Nucleus Biogenesis, Structure and Function
the N-terminal domains of the histones
associate with DNA and allow interaction
between adjacent nucleosomes.
4.1.3
Euchromatin and Heterochromatin
As the chromatin Fber is the template
for functions such as DNA replication
and RNA transcription, the importance
of this DNA–protein complex cannot
be overstated. In particular, it is crucial
to recognize how modiFcation of chro-
matin structure impacts on the behavior
of chromatin. Broadly speaking, chro-
matin within a mammalian nucleus can
be characterized as euchromatin or het-
erochromatin. The former is ostensibly
composed of chromosomal regions that
have a high density of transcriptionally ac-
tive genes. Euchromatin corresponds to
chromosomal regions that can be classi-
Fed as R-bands using cytological criteria.
These are slightly GC-rich (because of
GC-islands associated with housekeeping
genes), have a high density of Alu-repeats
and are duplicated in the early part of
S-phase. Heterochromatin, in contrast,
has many fewer transcribed genes, occu-
pies chromosomal G- and C-bands and
is replicated in the second half of S-
phase. Euchromatin and heterochromatin
have distinct features that correlate with
these characteristics. Perhaps the most
diagnostic among these is the ease with
which the different chromatin popula-
tions can be cut with nucleases. Hence,
euchromatin is readily digested with en-
zymes such as DNase – it is classiFed
as being DNase sensitive – whereas het-
erochromatin is relatively insensitive. This
ease of digestion reflects the accessi-
bility of DNA to DNAse – euchromatin
has a loose or open chromatin struc-
ture, whereas heterochromatin is more
compact. These basic chromatin states
correlate with a functional status, which
reflects how transcribed genes are packed
into chromatin that is modiFed to allow
transcription to occur.
4.1.4
Histone Modifcations
As chromatin modiFcation is central to
the control of gene expression, it is
important to understand at least the basic
principles of this process. It has been
known for many years that the histones are
subject to a wide range of modiFcations.
These include acetylation, methylation,
phosphorylation, ADP-ribosylation, and
ubiquination. These modiFcations are
used to generate and stabilize the different
classes of chromatin, modulate chromatin
structure throughout the cell cycle, and
control histone turnover. In terms of gene
expression, acetylation of the N-terminal
domains
of
histones – particularly
H3
and H4 – is of the greatest importance.
These
lysine-rich
domains
each
have
numerous lysine residues that are targets
for acetylation. Acetylation serves to reduce
the stability of the nucleosome complex so
that the DNA is more readily accessible to
the transcription machinery.
The mechanisms by which histone acety-
lation are controlled are extremely com-
plex. Levels of acetylation at any locus
are dictated by the combined activities of
histone acetyl transferases (HATs) and his-
tone deacetylase complexes (HDACs). The
activity of these large protein complexes
is determined, in turn, by mechanisms
that control their recruitment to differ-
ent nuclear sites. The protein p300/CBP
is a global transcriptional regulator that
binds to enhancers within many gene loci
and contains a HAT activity that is ca-
pable of acetylating speciFc sites in all
the core histones and other transcrip-
tion factors to stimulate transcription. In
addition, complexes such as PCA± in-
teract with p300/CBP, SCR1/ACTR and
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