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Gene Expression

Genes encode proteins and proteins dictate cell function. Therefore, the thousands of genes expressed in a particular cell determine what that cell can do. Moreover, each step in the flow of information from DNA to RNA to protein provides the cell with a potential control point for self-regulating its functions by adjusting the amount and type of proteins it manufactures.

At any given time, the amount of a particular protein in a cell reflects the balance between that protein's synthetic and degradative biochemical pathways. On the synthetic side of this balance, recall that protein production starts at transcription (DNA to RNA) and continues with translation (RNA to protein). Thus, control of these processes plays a critical role in determining what proteins are present in a cell and in what amounts. In addition, the way in which a cell processes its RNA transcripts and newly made proteins also greatly influences protein levels.

How Is Gene Expression Regulated?

The amounts and types of mRNA molecules in a cell reflect the function of that cell. In fact, thousands of transcripts are produced every second in every cell. Given this statistic, it is not surprising that the primary control point for gene expression is usually at the very beginning of the protein production process — the initiation of transcription. RNA transcription makes an efficient control point because many proteins can be made from a single mRNA molecule.

Transcript processing provides an additional level of regulation for eukaryotes, and the presence of a nucleus makes this possible. In prokaryotes, translation of a transcript begins before the transcript is complete, due to the proximity of ribosomes to the new mRNA molecules. In eukaryotes, however, transcripts are modified in the nucleus before they are exported to the cytoplasm for translation.

Eukaryotic transcripts are also more complex than prokaryotic transcripts. For instance, the primary transcripts synthesized by RNA polymerase contain sequences that will not be part of the mature RNA. These intervening sequences are called introns, and they are removed before the mature mRNA leaves the nucleus. The remaining regions of the transcript, which include the protein-coding regions, are called exons, and they are spliced together to produce the mature mRNA. Eukaryotic transcripts are also modified at their ends, which affects their stability and translation.

Of course, there are many cases in which cells must respond quickly to changing environmental conditions. In these situations, the regulatory control point may come well after transcription. For example, early development in most animals relies on translational control because very little transcription occurs during the first few cell divisions after fertilization. Eggs therefore contain many maternally originated mRNA transcripts as a ready reserve for translation after fertilization (Figure 1).

On the degradative side of the balance, cells can rapidly adjust their protein levels through the enzymatic breakdown of RNA transcripts and existing protein molecules. Both of these actions result in decreased amounts of certain proteins. Often, this breakdown is linked to specific events in the cell. The eukaryotic cell cycle provides a good example of how protein breakdown is linked to cellular events. This cycle is divided into several phases, each of which is characterized by distinct cyclin proteins that act as key regulators for that phase. Before a cell can progress from one phase of the cell cycle to the next, it must degrade the cyclin that characterizes that particular phase of the cycle. Failure to degrade a cyclin stops the cycle from continuing.

A schematic of a eukaryotic cell and its interior shows the transcription of DNA to RNA, and the translation of RNA to protein in four steps: transcription, RNA splicing, nuclear export, and translation. Each step is represented by a labeled arrow. Transcription of a DNA template to a pre-mRNA and the splicing of the pre-mRNA into a mature mRNA are shown inside the cell nucleus. The nuclear export brings the mature mRNA to the cytoplasm, where the mature mRNA message is translated into a protein.
Figure 1: An overview of the flow of information from DNA to protein in a eukaryote
First, both coding and noncoding regions of DNA are transcribed into mRNA. Some regions are removed (introns) during initial mRNA processing. The remaining exons are then spliced together, and the spliced mRNA molecule (red) is prepared for export out of the nucleus through addition of an endcap (sphere) and a polyA tail. Once in the cytoplasm, the mRNA can be used to construct a protein.
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How Do Different Cells Express the Genes They Need?

Only a fraction of the genes in a cell are expressed at any one time. The variety of gene expression profiles characteristic of different cell types arise because these cells have distinct sets of transcription regulators. Some of these regulators work to increase transcription, whereas others prevent or suppress it.

Normally, transcription begins when an RNA polymerase binds to a so-called promoter sequence on the DNA molecule. This sequence is almost always located just upstream from the starting point for transcription (the 5' end of the DNA), though it can be located downstream of the mRNA (3' end). In recent years, researchers have discovered that other DNA sequences, known as enhancer sequences, also play an important part in transcription by providing binding sites for regulatory proteins that affect RNA polymerase activity. Binding of regulatory proteins to an enhancer sequence causes a shift in chromatin structure that either promotes or inhibits RNA polymerase and transcription factor binding. A more open chromatin structure is associated with active gene transcription. In contrast, a more compact chromatin structure is associated with transcriptional inactivity (Figure 2).

Some regulatory proteins affect the transcription of multiple genes. This occurs because multiple copies of the regulatory protein binding sites exist within the genome of a cell. Consequently, regulatory proteins can have different roles for different genes, and this is one mechanism by which cells can coordinate the regulation of many genes at once.

A two-part schematic shows how an activator protein binds DNA to initiate transcription. A linear DNA molecule is shown above a DNA molecule folded to form a loop. The enhancer sequence, promoter sequence, and site of transcription are represented by colored shading on both DNA molecules, and an activator molecule is represented by a globular structure. The interaction between RNA polymerase, a mediator protein, and the activator protein are shown in the bottom illustration.
Figure 2: Modulation of transcription
An activator protein bound to DNA at an upstream enhancer sequence can attract proteins to the promoter region that activate RNA polymerase (green) and thus transcription. The DNA can loop around on itself to cause this interaction between an activator protein and other proteins that mediate the activity of RNA polymerase.
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How Is Gene Expression Increased or Decreased in Response to Environmental Change?

In prokaryotes, regulatory proteins are often controlled by nutrient availability. This allows organisms such as bacteria to rapidly adjust their transcription patterns in response to environmental conditions. In addition, regulatory sites on prokaryotic DNA are typically located close to transcription promoter sites — and this plays an important part in gene expression.

A three-part schematic shows how a repressor protein can inhibit transcription by preventing RNA polymerase from binding DNA. Part 1 shows the layout of a linear region of DNA. The operator is represented by colored shading on the DNA molecule and spans three nucleotides. The site of transcription is shaded a different color, and an arrow points from left to right above the shading to show the direction transcription proceeds. Part 2 shows the positions of an inactive repressor protein and RNA polymerase relative to a DNA molecule when transcription is occurring. Part 3 shows the positions of an active repressor protein and RNA polymerase in relation to a DNA molecule when transcription is repressed.
Figure 3: Transcription repression near the promoter region.
Molecules can interfere with RNA polymerase binding. An inactive repressor protein (blue) can become activated by another molecule (red circle). This active repressor can bind to a region near the promoter called an operator (yellow) and thus interfere with RNA polymerase binding to the promoter, effectively preventing transcription.
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For an example of how this works, imagine a bacterium with a surplus of amino acids that signal the turning "on" of some genes and the turning "off" of others. In this particular example, cells might want to turn "on" genes for proteins that metabolize amino acids and turn "off" genes for proteins that synthesize amino acids. Some of these amino acids would bind to positive regulatory proteins called activators. Activator proteins bind to regulatory sites on DNA nearby to promoter regions that act as on/off switches. This binding facilitates RNA polymerase activity and transcription of nearby genes. At the same time, however, other amino acids would bind to negative regulatory proteins called repressors, which in turn bind to regulatory sites in the DNA that effectively block RNA polymerase binding (Figure 3).

The control of gene expression in eukaryotes is more complex than that in prokaryotes. In general, a greater number of regulatory proteins are involved, and regulatory binding sites may be located quite far from transcription promoter sites. Also, eukaryotic gene expression is usually regulated by a combination of several regulatory proteins acting together, which allows for greater flexibility in the control of gene expression.

A schematic shows three transcriptional regulator proteins on a DNA molecule. The DNA molecule is folded in on itself to form loops and each regulator protein is bound to the apex of a DNA loop and interacting with a single mediator protein bound to RNA polymerase. RNA polymerase is in turn bound to a region of DNA between the promoter sequence and the site of transcription.
Figure 4: The complexity of multiple regulators
Transcriptional regulators can each have a different role. Combinations of one, two, or three regulators (blue, green, and yellow shapes) can affect transcription in different ways by differentially affecting a mediator complex (orange), which is also composed of proteins. The effect is that the same gene can be transcribed in multiple ways, depending on the combination, presence, or absence of various transcriptional regulator proteins.
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As previously mentioned, enhancer sequences are DNA sequences that are bound by an activator protein, and they can be located thousands of base pairs away from a promoter, either upstream or downstream from a gene. Activator protein binding is thought to cause DNA to loop out, bringing the activator protein into physical proximity with RNA polymerase and the other proteins in the complex that promote the initiation of transcription (Figure 4).

Different cell types express characteristic sets of transcriptional regulators. In fact, as multicellular organisms develop, different sets of cells within these organisms turn specific combinations of regulators on and off. Such developmental patterns are responsible for the variety of cell types present in the mature organism (Figure 5).

A pedigree diagram shows how transcription factors influence the identities of four generations of cells. A single cell containing a nucleus is shown dividing to form two new cells (a second generation). Each of the two second-generation cells then divides to form two new cells, so this third generation has four cells. Each of the four third generation cells then divides to form two cells, for a total of eight fourth generation cells. The variable expression of transcription factors in each generation of cells is represented by the presence or absence of red, green, and yellow colored circles in their cytosol.
Figure 5: Transcriptional regulators can determine cell types
The wide variety of cell types in a single organism can depend on different transcription factor activity in each cell type. Different transcription factors can turn on at different times during successive generations of cells. As cells mature and go through different stages (arrows), transcription factors (colored balls) can act on gene expression and change the cell in different ways. This change affects the next generation of cells derived from that cell. In subsequent generations, it is the combination of different transcription factors that can ultimately determine cell type.
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To live, cells must be able to respond to changes in their environment. Regulation of the two main steps of protein production — transcription and translation — is critical to this adaptability. Cells can control which genes get transcribed and which transcripts get translated; further, they can biochemically process transcripts and proteins in order to affect their activity. Regulation of transcription and translation occurs in both prokaryotes and eukaryotes, but it is far more complex in eukaryotes.


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