Cell Nucleus Biogenesis, Structure and Function
other DNA-binding activators to stimulate
transcription by histone acetylation, pre-
dominantly in histone H3. Components
of the multi-subunit general transcription
factors TFIID and TFIIIC also have HAT
activities that modify histones H3 and
H4 to stimulate transcription and other
HAT activities are associated with the
elongating polymerase holoenzyme com-
plexes. The patterns of histone acetylation
that might be developed in response to
these different activities can be extremely
complex; different HATs have numerous
potential acetylation targets and different
preferences for the various sites. Major
modi±cations that correlate with an active
chromatin status include acetylation of his-
tone H3 at lysines 9 and 14 and H4 at lysine
5. Speci±city for particular sites in chro-
matin is a product of the mechanisms of
association of each HAT with chromatin.
The bromodomain of these proteins is
thought to play a role in this process.
Histone acetylation in euchromatin cor-
relates with gene activity. In contrast,
inactive, heterochromatin has lower lev-
els of acetylation and much higher levels
of histone methylation and phosphoryla-
tion. The human suppressor of variega-
tion protein SUV39H1 encodes a histone
methyltransferase (HMT) that selectively
methylates histone H3 at lysine 9. This ac-
tivity is dependent on a SET domain within
the protein. This particular histone mod-
i±cation induces high-af±nity binding of
the heterochromatin protein HP1, through
chromodomains. The other major group
of heterochromatin proteins, the poly-
comb group (Pc-G) proteins, are known
to recruit protein complexes with histone
deacetylase activity. Pc-G proteins and an-
tagonizing proteins of the trithorax group
(trx-G) together play a fundamental role
in modulating the dynamic transition be-
tween inactive and active chromatin states.
ATP-dependent Chromatin
Remodeling Machines
Chromatin status and the activity of com-
plexes that catalyze the modi±cation of
the histones are also influenced by the
activity of a variety of protein complexes
that perform ATP-dependent chromatin
remodeling. These complexes were ±rst
described in studies to understand the
control of mating type switching (SWI)
and sucrose fermentation (SNF for su-
crose nonfermenting) in yeast. Chromatin
remodeling was recognized as a major fac-
tor in these two processes and has since
been shown to be a fundamental reg-
ulator of gene expression. Examples of
the remodeling machines in human cells
include the human SWI/SNF complex,
NURD (nucleosome remodeling histone
deacetylase complex) and RSF (remodeling
and spacing factor). These multiprotein
complexes operate through different chro-
matin binding domains. hSWI/SNF has
a bromodomain, NURD chromodomains
and RSF a SANT domain.
These chromatin remodeling machines
serve to increase the local dynamic prop-
erties of chromatin. DNA and histones
in chromatin make so many contacts that
the nucleosomes they form are inherently
stable structures. Nucleosomes can form
on almost all stretches of DNA of suf±-
cient length, though the need to fold the
DNA duplex over the nucleosome surface
does impose constraints on the way chro-
matin forms. In particular, the center of
the dyad axis in a nucleosome has a re-
gion of DNA that is distorted or kinked in
order to make the necessary contacts with
the histones of the nucleosome core. AT
bases in DNA are preferred at this location.
Other mechanisms exist to position the nu-
cleosome in a speci±c way – the binding
of a factor with DNA prior to establish-
ing local chromatin structure would be an
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