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12.3: Eukaryotic Gene Regulation

Like prokaryotes, transcriptional regulation in eukaryotes involves both cis-elements and trans-factors, only there are more of them and they interact in a more complex way.  A diagram of a typical eukaryotic gene, including several types of cis-elements, is shown in Figure 12.7.

12.3.1 Proximal Regulatory sequences.

As in prokaryotes the RNA polymerase binds to the gene at its promoter to begin transcription. In eukaryotes, however, RNApol is part of a large protein complex that includes additional proteins that bind to one or more specific cis-elements in the promoter region, including GC-rich boxes, CAAT boxes, and TATA boxes.  High levels of transcription require both the presence of this protein complex at the promoter, as well as their interaction with other trans-factors described below. The approximate position of these elements relative to the transcription start site (+1) is shown in Figure 12.7, but it should be emphasized that the distance between any of these elements and the transcription start site can vary, but are typically within ~200 base pairs of the start of transcription. This contrasts the next set of elements. 

12.3.2   Distal Regulatory elements

Even more variation is observed in the position and orientation of the second major type of cis-regulatory element in eukaryotes, which are called enhancer elements.  Regulatory trans-factor proteins called transcription factors bind to enhancer sequences, then, while still bound to DNA, these proteins interact with RNApol and other proteins at the promoter to enhance the rate of transcription.  There are a wide variety of different transcription factors and each recognizes a specific DNA sequence (enhancer element) to promote gene expression in the adjacent gene under specific circumstances.  Because DNA is a flexible molecule, enhancers can be located near (~100s of bp) or far (~10K of bp), and either upstream or downstream, from the promoter (Figure 12.7 and 12.8).

Figure 12.7:
Structure of a typical eukaryotic gene.  RNA polymerase binding may involve one or more cis-elements within the proximal region of a promoter (green boxes). Enhancers (yellow boxes) may be located any distance upstream or downstream of the promoter and are also involved in regulating gene expression.  The processing of a primary transcript to a mature mRNA is also shown.  (Origianl-Deyholos-CC:AN)

Figure 12.8: A transcription factor (yellow) bound to an enhancer that is located far from a promoter.  Because of the flexibility of the DNA molecule, the transcription factor and RNApol are able to interact physically, even though the cis-elements to which they are bound are located far apart.  In eukaryotic cells, RNApol is actually part of a large complex of proteins (not shown here) that assembles at the promoter. (Origianl-Deyholos-CC:AN)

12.3.3 Example 1:  Drosophila yellow gene

The yellow gene of Drosophila provides an example of the modular nature of enhancers.  This gene encodes an enzyme in the pathway that produces a dark pigment in the insect’s exoskeleton. Mutants have a yellow cuticle rather than the wild type darker pigmented cuticle.  (Why call the gene “yellow”: recall that genes are often named after their mutant phenotype.)  Figure 12.9 shows three enhancer elements (left side - wing, body, mouth), each binds a different tissue specific transcription factor to enhancer transcription of yellow+ in that tissue and makes the pigment. So, the wing cells will have a transcription factor that binds to the wing enhancer to drive expression; likewise in the body and mouth cells. Thus, specific combinations of cis-elements and trans-factors control the differential, tissue-specific expression of genes.  This type of combinatorial action of enhancers is typical of the transcriptional activation of most eukaryotic genes: specific transcription factors activate the transcription of target genes under specific conditions.

Figure 12.9:
Tissue-specific cis-regulatory elements within a simplified representation of the yellow gene of Drosophila.  (Origianl-Deyholos-CC:AN)

While enhancer sequences promote expression, there is an oppositely acting type of element, called silencers. These elements function in much the same manner, with transcription factors that bind to DNA sequences, but they act to silence or reduce transcription from the adjacent gene.

Again, a gene’s expression profile (transcription level, tissue specific, temporal specific) is a combination of various enhancer and silencer elements.

12.3.4 Example 2:  Gal4-UAS system from yeast – a genetic tool

Genetic researchers have taken advantage of a yeast distal enhancer sequence to make the GAL4-UAS system, a powerful technique for studying the expression of genes in other eukaryotes. It relies on two parts: a “driver” and a “responder” (Figure 12.10). The driver part is a gene encoding a yeast transcriptional activator protein called Gal4. It is separate from the responder part, which contains the enhancer sequence, or upstream activation sequence (UAS, as it is called in yeast) to which the Gal4 protein specifically binds. This UAS is placed upstream (using genetic engineering) from a promoter transcribing a reporter gene, or other gene of interest, such as GFP (green fluorescent protein).

Figure 12.10:
The GAL4-UAS system. The driver, with a wing enhancers, expresses the Gal4 protein that then binds to the UAS element upstream of a marker gene, GFP. This would express the GFP in the wing tissues.  The modular aspect of this system would let the wing enhancer be replaced by any other enhancer and the GFP marker replaced with any other gene.  (Origianl-Locke-CC:AN)

Both parts must be present in the same cell for the system to express the responder gene. If the driver is absent, the responder product will not be expressed. However, both are in the same cell (or organism) the pattern of expression of the driver part will induce the responder part’s expression in the same pattern.             

This system works is a variety of eukaryotes, including humans. It has been especially well exploited in Drosophila where 100’s (1,000’s ? ) of differently expressing driver lines are available. These lines permit the tissue specific expression of any responder gene to examine its effect on development.