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Welcome everyone to Chapter 5 of
this short talk series on
nuclear receptors as
therapeutic targets.
In Chapter 5, we will
continue with the topic of
the structural and
molecular mechanisms
of nuclear receptor activity
and we will look at
transcriptional activation and
repression as well as
coregulator interactions.
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We have seen in
previous chapters that
nuclear receptors differ in
their cellular localization.
Type I nuclear receptors
only translocate to
the nucleus and bind to DNA
after ligand binding,
as shown on the left.
Type II, III, and IV nuclear
receptors on the right
can bind to DNA in the absence
of ligands, and this has
consequences on their
effects on transcription.
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When Type II, III, and
IV nuclear receptors
bind to DNA in the
absence of a ligand,
they typically recruit
corepressor complexes.
These corepressor complexes
containing, for example,
NCOR, which stands for
nuclear receptor corepressor,
on the one hand,
prevent the binding of
coactivators and
on the other hand,
often exhibit histone
deacetylase activity
leading to chromatin compaction.
Hence, corepressor
complexes recruited
to nuclear receptors inhibit
gene expression by
several mechanisms
meaning that many
nuclear receptors of
Type II, III, and IV,
which can bind to DNA
in unliganded state can cause
transcriptional repression.
In the activated state
shown here on the right,
the corepressor complex gets
replaced by a
coactivator complex.
These recruited
coactivators can mediate
histone acetylation and recruit
the transcriptional machinery
to activate transcription.
For many nuclear receptors,
this exchange of
corepressors by coactivators
happens in a
ligand-induced fashion,
and we will have a look at these
underlying mechanisms
in the next chapter.
Other Type II, III, and IV
nuclear receptors, for example,
retinoic acid receptor-related
orphan receptors
adopt the activated state with
bound coactivator complex
also in the absence
of ligands and
hence, constitutively
activate transcription
also without a ligand signal.
As indicated, the corepressor
