Purpose of Regulating Gene Expression

We know by now that most of the cells in your body have the exact same DNA. So what makes a cell in your toe different from a cell in your liver? If they contain the same information, shouldn't they do the same things? The answer to this mystery is all about gene expression - which genes each cell turns on and which ones it turns off. In fact, this is how stem cells differentiate into different cells. Stem cells are basically blank canvases on which anything (or almost anything) can be painted. Depending on what genes get expressed via transcription and translation, two cells with vastly different jobs and structures can have the same DNA.

In addition, cells need to be able to change things when conditions change. Last I checked, the world was an unpredictable place, and cells must be able to acclimate. For instance, if a new food source becomes available, a cell would benefit from being able to properly digest it. But, if that food was absent, a cell shouldn't waste the energy producing the enzymes to break it down.

TURNING GENES ON AND OFF

Regulation at the  DNA level ( see more on epigenetics page)

In histone acetylation, acetyl groups are attached to positively charged lysines in histone tails. This loosens chromatin structure, thereby promoting the initiation of transcription

 The addition of methyl groups (methylation) can condense chromatin; the addition of phosphate groups (phosphorylation) next to a methylated amino acid can loosen chromatin

Regulation at  Transcription Step:   Regulatory Sequences

Regulatory sequences are stretches of DNA that interact with regulatory proteins to control transcription. There are multiple types of regulatory sequences, but we will focus on promoters, terminators, and enhancers primarily.

GENE REGULATION IN DIFFERENT TISSUES

Virtually all cells in the body have the same genetic makeup*, but not all genes are expressed in all tissues at all times. 

• Whether a gene is expressed is dependent on the regulatory switches that the gene possesses, and the activators or repressor proteins present in that cell. 

• Activators bind to regulatory switches in a sequence-specific manner. The binding of the activators to the switches activates transcription. 

• Some genes, especially genes involved in body development, have multiple switches. Each switch independently regulates the expression of the gene in different parts of the body at different times in the animal’s life cycle. 

• The presence of multiple switches enables the same gene to be used many times in different contexts and thus greatly expands the functional versatility of individual genes.

 • Mutations in regulatory switches affect the expression of a particular gene in a particular tissue without affecting the gene’s protein product (shape and function). 

• Changing the expression of a gene involved in body development can have profound effects on shaping the body. (* There are some notable exceptions: 

(1) Mature red blood cells have no DNA. 

(2) Germ line cells (sperm and egg) have half the genetic material. 

(3) B cells, which are part of the immune system, have DNA that has been rearranged to make antibodies. 

(4) Cells acquire somatic mutations. In some cases, these mutations confer a selective advantage for that cell and that mutation will be fixed in a set population of cells, like in the case of cancer cells.)

Example:  The Case of Stickleback Fish

This film explores how mutations in gene regulatory regions have resulted in major changes in the anatomy of freshwater populations of stickleback fish.

Many freshwater populations of sticklebacks lack the long spines that project from the pelvis of their marine relatives. These spines are important in the ocean for fending off large predators, so why were they lost in freshwater populations? The film tells the story of how David Kingsley, Michael Bell, and other scientists have identified key genes and genetic switches responsible for the evolution of this remarkable body transformation. Scientists have even documented similar evolutionary changes that occurred in the past, by studying a remarkable fossil record from the site of what was an ancient lake ten million years ago.

Gene Regulation and Expression  in Tissues of the Stickleback

As you saw in the film, the presence or absence of pelvic spines in the stickleback fish is controlled by whether the Pitx1 gene is expressed in the pelvic tissue. 

However, the Pitx1 protein is actually important in building other body parts and is therefore expressed in multiple tissues at specific times. How is Pitx1 expressed in different tissues? The Pitx1 gene has multiple regulatory switches that control the expression of the gene in different tissues: the pituitary, jaw, and pelvic tissues. Having multiple switches enables Pitx1 to be used many times in different contexts and expands the versatility of that gene. These switches are part of the DNA upstream of the Pitx1 coding region. Activators present in a particular tissue bind to a specific sequence on the DNA and turn Pitx1 on in the appropriate tissues. 

For example, in the cells that develop into the pelvis there is a specific activator (activator 2) that binds in a sequence-specific manner to the pelvic switch to transcribe Pitx1 in that tissue. 

In the jaw, there is a different activator (activator 1) that binds to a different sequence called the jaw switch to turn on Pitx1 in the jaw tissue. 

However, Pitx1 is not transcribed in the eyes because it does not have a sequence that can bind to activators present in the eyes. As you can see, while the DNA is the same in all cells of the body, the activators that are present differ from tissue to tissue. By having multiple regulatory switches, Pitx1 can be used many times in different tissues to build specific body parts.

Operons

An operon is a section of DNA under the control of one promoter. So, this section of DNA can be more easily turned on or off. There are two major types of operons: inducible and repressible.

Under normal circumstances when expression isn't occurring [so it is turned OFF] (left side of diagram), there is a repressor active that essentially blocks the RNA polymerase (shown in white) from transcribing the gene. In order to transcribe the gene, that repressor must be removed. Think of the repressor as a big roadblock on the railroad track that is the DNA.

Inducible operons are most common for proteins that are used to break down food (catabolic processes).

When the gene is expressed, an inducer binds to the repressor, making the repressor inactive. Thus, the roadblock is removed and the gene can be transcribed (expressed).

So, to summarize, inducible operons are normally OFF (not expressed), and must be turned ON if they are to be expressed.

Under normal circumstances when expression is occurring [so it is turned ON] (left side of diagram), there is a repressor, but it is inactive. It is simply floating around waiting for its missing piece.

Repressible operons are most common for proteins that are used to build up organic molecules (anabolic processes).

When the gene is not expressed, a corepressor binds to the repressor, making the repressor active. Thus, the roadblock is instated and the gene can no longer be transcribed (expressed).So, to summarize, repressible operons are normally ON (expressed), and must be turned OFF.