Gene Expression: Overview of Control

To understand transcriptional regulation, consider the structure of a typical eukaryotic gene, shown in Figure 3. The promoter of a gene is the binding site for a group of general transcription factors and for RNA polymerase. Transcription begins when a complex of proteins called TFIID binds to a promoter. The sequential binding of other general transcription factors and RNA polymerase follows. A protein tail tethers the RNA polymerase to the general transcription complex. When the general transcription factor TFIIH phosphorylates this tail, the RNA polymerase is released and moves along the DNA to begin transcription.

Figure 3. Structure of a typical eukaryotic gene.

These steps are identical for essentially all genes. However, the rate at which each of the steps occurs can be influenced by the presence or absence of other, gene-specific transcription factors. It is these other factors, often called gene regulatory proteins, that give the cell the ability to turn some genes on and others off. In contrast to the few general transcription factors, which assemble on the promoters of all genes, there are thousands of gene regulatory proteins. The regulatory proteins bound to a gene vary from gene to gene, and each is usually present at low levels in the cell.

Binding sites for these additional regulatory proteins are usually located upstream from the promoter. Surprisingly, these binding sites can be located some distance from the promoter and still regulate transcription. It is thought that this action at a distance can occur because the DNA between the regulatory sequence and the promoter can loop out, to allow the regulatory protein to contact the promoter, as shown in Figure 4.

Regulatory proteins are classified as either activators or repressors. Activators increase the rate of transcription, whereas repressors decrease it. The DNA sequences that bind activator proteins are called "enhancer elements," and those that bind repressor proteins are "repressor elements" or "silencer elements."

Many regulatory proteins have at least two distinct regions or domains, as shown in Figure 5. One domain binds to a specific DNA sequence. The other domain typically contacts the general transcription machinery assembled at the promoter. In one class of activating proteins, the activation domain contains a cluster of negatively charged (acidic) amino acids. Scientists believe acidic transcriptional activators accelerate the assembly of general transcription factors on the promoter. This is just one way a transcriptional activator can work. For instance, other regulatory proteins affect how tightly the gene is packaged within chromatin. Opening up the chromatin allows the transcription machinery to more quickly gain access to the promoter.

Gene regulatory proteins bind to the DNA when it is in a double-helical state. They recognize a specific DNA sequence by forming hydrogen bonds to chemical groups on the outside of the DNA. These proteins often contain common identifiable structural "motifs" that directly contact specific DNA sequences.

Figure 4. A regulatory element contacting the promoter by looping out the intervening DNA.