Chromatin remodelling

The organization of chromatin into nucleosomes is
an essential feature in the regulation of transcription.
Nucleosomes are transcriptional repressors because
they impede access of the basal transcription machinery
to the core promoter. Of particular signifi cance,
nucleosomes virtually prevent the binding of TBP
to the TATA box in vitro, and TBP does not associate
with the core promoter in vivo in the absence of
a functional activator. The inability of TBP to bind
nucleosomal DNA means that recruitment of the
basal transcription machinery is excluded. On the
other hand, nucleosomes have only a modest inhibitory
effect on the binding of activator proteins
to their upstream enhancers. The repressive action of
nucleosomes is important in closing off those parts of
the genome that need to be transcriptionally silenced.
When it becomes necessary for a gene to be expressed,
changes in cell physiology elicit a remodelling of chromatin,
which allows binding of transcription factors
at promoters. Two important chromatin remodelling
systems have been studied. In one system, the changes
in chromatin structure are mediated by ATP-driven
Swi/Snf proteins; the other system involves the posttranslational
modifi cation of core histones by acetylation.
Both systems disrupt histone–DNA interactions
in a transient and reversible manner.
Swi/Snf remodelling proteins
Members of the Swi/Snf family of chromatin remodelling
proteins comprise highly conserved multisubunit
complexes of ~2 MDa – huge proteins about half
the size of a ribosome. In yeast Swi/Snf, the Swi2/Snf2
subunit is an ATPase that contains sequence motifs
closely related to those found in DNA helicases. Although
Swi/Snf does not catalyse DNA unwinding, it
The genetic control of protein synthesis and its regulation by nuclear hormone receptors 123
may function in a manner similar to helicase. That is, it
may move along a nucleosome in a wave-like manner
using the energy derived from the hydrolysis of ATP
(Pazin & Kadonaga, 1997). This movement is accompanied
by a partial and localized alteration of chromatin
structure in a manner that permits the binding
of site-specifi c transcription factors. Although the
mechanism by which Swi/Snf functions has not yet
been elucidated, it appears that these remodelling
proteins increase accessibility of transcription factors
to DNA without displacing histones. Swi/Snf could
either perturb but not fully disrupt the structure of
nucleosome core particles or they could infl uence the
spacing of nucleosome arrays. With regard to the latter
possibility, the twisting of DNA at the edges of the
nucleosome may cause the nucleosome to slide along
the DNA (Varga-Weisz & Becker, 1998). The accessible
chromatin reverts to an inaccessible form unless a
transcription factor binds to the DNA.