Figure 7–9 Transcription regulators and cis-regulatory sequences. (A) Depiction of the cis-regulatory sequence for nanog, a homeodomain family member that is a key regulator in embryonic stem cells. this “logo” form (see figure 6–12) shows that the protein can recognize a collection of closely related DnA sequences and gives the preferred nucleotide pair at each position. Cis-regulatory sequences are “read” as double-stranded DnA, but only one strand typically is shown in a logo.
(B) representation of the cis-regulatory sequence as a colored box. (C) Many transcription regulators form dimers (homodimers) and heterodimers. in the example shown, three different DnAbinding specificities are formed from two transcription regulators.
Figure 7–10 Occupancy of a cisregulatory sequence by a transcription regulator. (A) noncooperative binding by a stable heterodimer. (B) Cooperative binding by components of a heterodimer that are predominantly monomers in solution. the shape of the curve differs from that of (A) because the fraction of protein in a form competent to bind DnA (the heterodimer) increases with increasing protein concentration.
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.