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The Theme of Regulation in Gene to Protein

"It was the best of times, it was the worst of times." No you aren't in English class and no we are not about to ask you about allegories, epigraphs, or allusions. What we will say though, is that maybe A Tale of Two Cities isn't too irrelevant to biology. It turns out that change and suffering isn't limited to the 18th century France. Imagine that.

Organisms, and the cells that comprise them, are constantly exposed to different conditions, good and bad. Adaption is critical for survival. Now if you are thinking of all-nighter video game marathons, rock concerts, sunbathing, and trips to Antarctica, and you are totally on track.

You can also think about a single-celled organism like yeast. A single cell sits on a grapevine, exposed to rain, wind, and drought. These conditions generate stressful situations for the cell, where food and water may not be as abundant or readily available. Extreme temperatures can also lead to non-ideal growing conditions.

Cells respond to changing conditions by changing the amount (and types) of proteins they produce. But wait, let's back up a little and talk about how the amount of a protein differs from one cell to another in the first place.

Different cells produce different amounts of proteins. Some proteins are uniquely expressed in certain cell types or organisms. Other times it is only the levels of proteins that are different. This straightforward concept best describes why each of the cells in your body is capable of playing the role it does. What we have told you is that the amount of any given protein differs from one cell to another. The amount may also be changed as the cell adapts to its environment. For example, a single celled organism exposed to high heat may start producing a type of protein that helps other proteins fold at the higher temperature.

That brings us to a basic question: how does a cell control the amount of protein it produces? You know all about transcription and translation now, so can you think of some ways that a regulatory system might work?

Not too long ago some of the world's top scientists thought it was by getting rid of DNA that the cell didn't need. Can you think of why this situation would be a bad solution for the cell? It is kind of like throwing out all of your winter clothes in summer because it is hot at the moment. Come wintertime you'd be a unhappy camper.

You've probably figured out that the cell can alter the transcription of RNAs and well as the translation of proteins to create the desired protein output. All of this work can be done without altering the amount or quantity of DNA in the cell. Without further ado, let's start talking about how transcription and translation can be modified to create different amounts of proteins.

Killing the Messenger

The cell can regulate the amount of protein produced by regulating the amount of mRNA; this is akin to killing the messenger. This way the cell doesn't need to make a whole bunch of RNA that it won't end up using. This is the method that is most commonly used to regulate the production of a protein.

One of the most common ways to control transcription is through the use of specific DNA binding factors. These proteins can recognize specific DNA sequences around the transcription start site. They can provide all sorts of levels of control, from a simple on and off switch, to more complex regulatory control. Think of a light on a dimming switch.

Let's start off with a simple switch first from…you guessed it…bacteria! Those little suckers are great at providing straightforward example of how transcription can be regulated. Sensing a pattern yet? Good. It is a general rule of thumb that eukaryotic processes are lot more complicated than prokaryotes. It is for this reason scientists like to study prokaryotic processes first. It is kind of like learning to ski on the bunny hills before jumping to Corbet. Insert link http://www.travelandleisure.com/articles/worlds-scariest-ski-slopes

What does gene control look like in prokaryotes like bacteria?

A lot of bacterial genes are arranged in operons, groupings of similar genes arranged in a similar location in the genome. These genes can be controlled all at once and even used to produce a single mRNA. Most often these genes are all involved in a particular process in the cell. Operons are often controlled by the regulatory sequences located adjacent to the gene. This type of regulation is called regulation in cis.

Psst…don't confuse operon with Oberon, the king of the fairies. You might remember that dude from Shakespeare's A Midsummer Night's Dream. He's the one that makes Titania fall in love with Bottom, a weaver wearing a donkey's head. I guess now that we think about it, operons and Oberon do have something in common. They are both all about control, but operons don't work though love potions. Thank goodness, too, because biology is complicated enough as it is without getting Cupid involved!

Alright, back to biology. Oftentimes RNA polymerase can't begin transcription without the assistance of regulatory DNA binding proteins. These proteins bind to the promoter in a special region called an operator. Since these binding proteins activate transcription through the RNA polymerase, they are called positive regulators, working through positive regulation. Alternatively, a different set of proteins, called transcriptional repressors, can bind to the genes preventing their transcription. This is a form of repression, or negative regulation. Regulation that involves the binding of either positive or negative regulatory proteins is called regulation in trans because they involve (trans) factors separate from the DNA sequence. We'll show you a real life example in a minute.

To keep cis and trans regulation straight, it may be helpful to remember the roots for cis and trans. Cis means "on the same side", while trans means "on the opposite side" or "beyond."

Most often genes are controlled by a combination of both positive and negative regulation. One of the most commonly described example in prokaryotes is the lac operon in E. coli. Genes in the lac operon are important for the transport and catabolism of the sugar lactose. Lactose is used as a sugar source only when the sugar glucose is absent or low. The operon is controlled such that the genes are only produced when lactose is present and glucose is absent. Both conditions must be met. Having lactose present is not enough.

The way the lac operon works is that the cAMP activator binds to the promoter of the lac operon only when lactose is present. The repressor binds when the cell has high levels of glucose. If the repressor is present RNA polymerase cannot bind. Only when the repressor is absent will the polymerase be able to bind. The cAMP activator is then required for the polymerase to actively transcribe the genes.

In some instances genes can be regulated by another type of regulation, called feedback regulation. In this case, the protein produced by a gene itself comes back to regulate the gene, either positively or negatively. These type of regulation provides a type of loop that allows the cell to gauge how much of a product it was produced. Pretty, pretty smart.

Yeah…that was the straightforward example….

Similar but more complicated regulation examples are also observed in eukaryotes. Why does regulation need to be so much more complicated in eukaryotes like us?

One reason for this situation is that eukaryotic genes are located within the context of higher order chromatin structure. Proteins that influence the structure of the DNA surrounding a gene can influence the ability for the polymerase and related factors to bind to the promoter. In fact, eukaryotic chromatin is often described as either heterochromatin or euchromatin.

Eukaryotic DNA is more open, and contains much of the regions of the genome that are actively transcribed. This "openness" is important for allowing regulatory proteins and RNA polymerase to bind. Alternatively, heterochromatin is more densely packed, and contains regions of the genome that are not likely to be transcribed. This "closed" structure of DNA can be compared to the difficulty in reading a novel with the cover closed. The DNA sequence is not just accessible for reading. Changing the chromatin structure surrounding a gene is another way that a cell can control a eukaryotic gene's transcription.

Another key difference in eukaryotes is the regulatory sequences are often located much farther away from genes. Eukaryotic activators, often called enhancers, can be located thousands of base pairs from the promoter. Activator proteins can bind to these DNA regions and bring them closer to the vicinity of the promoter. This can influence the ability of the polymerase and transcription factors to bind. Repressor proteins can work by a similar long distance mechanism in eukaryotes. Complicated stuff. No one said being a biologist was easy.

Looking Beyond the Messenger

As we mentioned earlier, it is also possible to prevent the production of a protein by repressing a step other than transcription. RNA splicing, RNA transport, RNA stability, and the progress of translation are all steps where regulation can and does occur. Let's talk about some examples of how these different steps can be regulated.

  • In prokaryotes, translational repressor proteins can bind to the Shine-Dalgarno sequence and prevent the ribosome from binding to the mRNA. Similarly eukaryotic translational repressors can bind to the mRNA either near the cap or tail, which interferes with the ability of the ribosome to initiate translation. Initiation factors can also be inactivated by post-translational modifications.
  • A RNA can be read and translated more than once. For this reason, the longer it stays around, the more likely it will be translated. Normally over time the poly-A tail on an RNA is gradually shortened. When the tail gets too short, a signal is sent for the RNA to be degraded. Regulatory proteins can interfere with this process to increase or decrease the stability of the RNA.
  • Perhaps one of the most dramatic examples of controlled localization occurs during development. In the early embryo, cell divisions often occur quickly, sometimes without the formation of membranes between the cells. RNA is often preferentially located in certain regions of the embryo. This phenomenon has been extensively studied in the fruit fly Drosophila. The localization of the RNAs to some region of the embryo, and its exclusion from other regions, is completely essential for determining what type of cells will be formed. In fact, this localization is also important for determining the polarity of an organism, or which end becomes the tail. This occurs because the protein products of the genes are restricted to the same regions. This is some cool stuff, and we highly recommend reading some more about regulation through RNA localization. Check out the best of the web for more.

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