Molecular Biology of the Cell by Bruce Alberts, Alexander Johnson, Julian Lewis, David Morgan, Martin Raff, Keith Roberts, Peter Walter by by Bruce Alberts, Alexander Johnson, Julian Lewis, David Morg

CONTROL OF TRANSCRIPTION BY SEQUENCE-SPECIFIC DNA-BINDING PROTEINS
379
for noncooperative binding; that is, at most protein concentrations, the cis-regulatory
sequence is either nearly empty or nearly fully occupied and rarely is somewhere
in between. A discussion of the mathematics behind cooperative binding is
given in Chapter 8 (see Figure 8–79A).
Nucleosome Structure Promotes Cooperative Binding of
Transcription Regulators
As we have just seen, cooperative binding of transcription regulators to DNA often
occurs because the monomers have only a weak affinity for each other. However,
there is a second, indirect mechanism for cooperative binding, one that arises
from the nucleosome structure of eukaryotic chromosomes.
In general, transcription regulators bind to DNA in nucleosomes with lower
affinity than they do to naked DNA. There are two reasons for this difference.
First, the surface of the cis-regulatory sequence recognized by the transcription
regulator may be facing inward on the nucleosome, toward the histone core, and
therefore not be readily available to the regulatory protein. Second, even if the
face of the cis-regulatory sequence is exposed on the outside of the nucleosome,
many transcription regulators subtly alter the conformation of the DNA when
they bind, and these changes are generally opposed by the tight wrapping of the
DNA around the histone core. For example, many transcription regulators induce
a bend or kink in the DNA when they bind.
We saw in Chapter 4 that nucleosome remodeling can alter the structure of
the nucleosome, allowing transcription regulators access to the DNA. Even without
remodeling, however, transcription regulators can still gain limited access to
DNA in a nucleosome. The DNA at the end of a nucleosome “breathes,” transiently
exposing the DNA and allowing regulators to bind. This breathing happens at a
much lower rate in the middle of the nucleosome; therefore, the positions where
the DNA exits the nucleosome are much easier to occupy (Figure 7–11).
These properties of the nucleosome promote cooperative DNA binding by
transcription regulators. If a regulatory protein enters the DNA of a nucleosome
and prevents the DNA from tightly rewrapping around the nucleosome core, it
will increase the affinity of a second transcription regulator for a nearby cis-regulatory
sequence. If the two transcription regulators also interact with each other
(as described above), the cooperative effect is even greater. In some cases, the
combined action of the regulatory proteins can eventually displace the histone
core of the nucleosome altogether.
Figure 7–11 How nucleosomes effect the
binding of transcription regulators.
histone core
transcription
+
regulator
+
“breathing”
(A)
cis-regulatory
sequence
this open form occurs
about 1/20th of the time
(B) compared to its affinity for naked DNA, a typical transcription regulator
will bind with 20 times lower affinity if its cis-regulatory sequence is
located near the end of a nucleosome
+ + +
(C)
a typical transcription regulator will bind
with roughly 200-fold less affinity
if its cis-regulatory sequence is located
in the middle of a nucleosome
(D)
one transcription regulator can destabilize the nucleosome, facilitating binding of another