Control of Gene Expression 
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• Introduction
• Control at the DNA
• Control of transcription
• The operon
• Hormonal control
• Gene packing and amplification
• Transcriptional editing
• Translational Control
• Polypeptide editing, repression, activation

Introduction

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If you think about the diploid cells in your body they generally have the same DNA since they are all originate from mitosis of an original zygote. Yet these cells have different shapes, sizes and functions. For instance, neurons are long cells, sometimes almost a meter long, that are involved in the transmission of information. On the other hand the epithelial cells, lining your cheek on the inside, are small perhaps 0.07mm, irregularly shaped and serve to protect the tissues of the cheek. Obviously these cells differ from one another in their phenotype and yet have the same DNA. The only way this can happen is if certain genes are expressed in cheek cells but not in the neurons and vice versa. A big question in biology is just how is gene expression controlled and at what level, the DNA, transcription, translation or perhaps after translation. 

This is a complex topic and we will look at some basic mechanisms of the control of gene expression in prokaryotes and eukaryotes. We will looks at many of the places along the way from the level of the DNA itself, then transcription, translation and all the way up to the activation of the final polypeptide where gene expression can be influenced. 

Control at the level of DNA

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The first level at which gene expression can be controlled is by altering the sequence of nucleotides in the DNA itself. This may seem odd because normally we think of all the cells in our body as having identical DNA but there are a few major exceptions. For example during development the cells that will eventually become the B cells in the immune system undergo a scrambling of the DNA in those regions of the DNA that will eventually give rise to the variable parts of the antibodies produced by the immune system. What happens is that as these cells are dividing during a certain brief phase of embryonic development, the DNA in these regions gets rearranged and different cells end up having different combinations of regions of DNA. Once this brief phase is finished the cells will continue to divide but the resulting daughter cells from a particular cell are identical to each other but not cells arising from parents with different combinations of genes. The result is literally thousands of clones of antibody producing cells, each clone producing a different antibody. 

Not to be out done,  some parasites, such as the trypanosomes that cause sleeping sickness, use DNA rearrangement to produce alternate surface antigens that cannot immediately be recognized by the host immune system. 

Control of transcription

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This type of control hinges on the idea that if a gene is not transcribed it's not able to be expressed. We'll look briefly at a system common in prokaryotes and the consider a slightly different set of systems that happens in eukaryotes. 

Operon

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In prokaryotes, genes are often grouped into arrangements called operons. Operons typically consist of three parts. First is a so called promoter(yellow) region. The RNA polymerase must attach to this region for transcription to begin. Next is an operator. This is a site where a repressor protein must attach to. If the repressor protein can attach to the operator, RNA polymerase cannot attach to the promoter and transcription of the genes in the third region of the operator can not happen. Again transcription must take place for a gene to be expressed. 

The classic example of an operon is the so called lac operon. Some bacteria are able to use lactose as a source of energy. This requires a set of enzymes coded for by a series of genes(pink) in the operon. The lac operon allows the transcription of these genes when lactose is present, and prevents transcription of these genes when lactose is absent. This works because of repressor protein coded for by a so called regulatory gene(purple). When lactose is absent, the regulatory protein has a shape that allows it to fit into the operator site. This prevents the RNA polymerase(dark green)from attaching to the promoter site(pale green). If the RNA polymerase cannot attach the promoter, it is unable to move down the operon to transcribe the enzyme coding genes. 
 

If lactose is present for the bacteria, a lactose molecule attaches to a binding site on the repressor protein. This alters the shape of the repressor protein so that it cannot fit on the operator site. Thus, the RNA polymerase can attach to the promoter, travel past the operator and transcribe the genes, making messenger RNA's for translation into the enzymes. 
 

Hormonal control

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In eukaryotes, transcription can also be controlled but not quite in the same way. For example steroid hormones typically act on their target cells by binding to a protein receptor located inside the target cell. The receptor-steroid complex then attaches to the DNA of the chromosome at an enhancer region of DNA. This activates a promoter region to which the RNA polymerase can bind allowing transcription of a set of genes. 

Gene packing and amplification

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A key feature of eukaryote gene expression is that if genes are hidden in someway so that the RNA polymerase can't get to them, they will not be transcribed. The classic example of this is the so called Barr Body. In mammals, remember that the female has two X chromosomes. During embryonic development, in different lines of cells one of the X chromosomes gets packed away into a structure called the Barr body. Thus its genes are not expressed.  For females heterozygous for an X linked characteristic, this means that the female is a mosaic with respect to which allele is expressed. This calico cats are generally female because the alleles for the black vs orange hair are on the X chromosome. XBXB individuals are black, XbXb individuals orange but XBXb individuals are calico reflecting random packing of either the XB or the Xb allele into the Barr body in different lines of cells. 

If a gene needs to be expressed then a set of reactions are set in motion which will expose that gene to RNA polymerase. In many chromosomes loops or puffs of exposed DNA are sites of heavy transcription. 

If there is heavy demand for a protein coded for by a gene or set of genes, the cell can make multiple copies of the gene so that more mRNA can be simultaneously made. This in affect allows genes to be amplified. A good example are the genes coding for ribosomal RNA(rRNA). In many organisms a mechanism exists for duplicating these genes for producing extra rRNA. In the interphase cells of certain  insects, chromosomes  have multiple copies side by side leading to an interphase chromosome visible using a light microscope! These polytene chromosomes have contributed greatly to our understanding of chromosome structure and to the study of evolution. 

Transcriptional editing(Introns, Exons)

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The transcript once made may in eukaryotic cells be edited. Eukaryote transcripts often contain non coding regions called introns which are spliced out. The remaining segments called exons are then joined together to make the final messenger RNA. Depending on the pattern of exons that are retained it is possible for a single gene to give rise to several polypeptides! 
Introns and exons are discussed further here. 

Translational Control

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  In some cases once the mRNA is available for translation translation can be encourages or suppressed. For example iron(Fe++) in cells is stored in a special protein called ferritin. If iron levels are low a repressor protein attaches to the mRNA for ferritin and prevents its translation into new protein. If iron levels in the cell rise, then some iron binds to the ferritin mRNA repressor protein, altering its shape and causing it to separate from the mRNA. Thus the mRNA can now be translated into ferritin needed to store the increased iron. Similar types of control operate for the synthesis of proteins made from different types of subunits such as hemoglobin. 

Polypeptide editing, repression, activation

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Even after translation(1), protein expression can be controlled or modified. For example many proteins are produced in an inactive form that must edited in order to become active. For example the insulin molecule is first produced as an inactive form comprised of a single polypeptide chain. To activate the insulin, the cell cuts the polypeptide chain into two chains joined by disulfide linkages. 

Often times the function of proteins is repressed by the presence of some compound in the environment. The binding of lactose to the lac operon repressor protein is an example of this.  In the inhibitory feedback systems found in many metabolic pathways, the product of a series of metabolic reactions may inhibit  the series by attaching to an enzyme involved in one of the earlier steps. 

Finally proteins may require activation by being combined with some other molecule. Cofactors which are required for the operation for many enzymes are a good example. Another example is the digestive enzyme pepsin produced by the stomach. When the enzyme is first produced by cells in the lining of the stomach it is in an inactive form called pepsinogen. Exposure to hydrochloric acid produced by other types of stomach lining cells converts pepsinogen into pepsin, its active form. Apparently this reaction is also autocatalytic in that pepsin also catalyses the conversion of pepsinogen into pepsin! 
 

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 pgd 03/15/00 Copyright(C) Paul Decelles 03/15/00