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6.1: Prokaryotic gene regulation - Biology

6.1: Prokaryotic gene regulation - Biology


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Learning Objectives

  • Define operon and describe how it differs from genes organized by single proteins.
  • Identify the functions of regulatory proteins, promoters, operators, cis- and trans-acting factors, and structural genes.
  • Distinguish between positive vs negative and inducible vs repressible operons.
  • Describe both positive and negative regulation of the lac operon.

Early insights into mechanisms of transcriptional regulation came from studies of E. coli by researchers Francois Jacob & Jacques Monod. In E. coli, and many other bacteria, genes encoding several different proteins may be located on a single transcription unit called an operon. The genes in an operon share the same transcriptional regulation, but are translated individually. Eukaryotes generally do not group genes together as operons (exception is C. elegans and a few other species).

How can an operon encode multiple proteins?

Think back to the steps involved in transcription and translation. Which steps will be altered if multiple proteins must be translated from a single transcript? How do you think this works?

Types of regulation

Operon can be turned "off" or "on" and be controlled protein activators or repressors. The four general categories of regulation can be described as:

Positive inducible operon:

An activator protein turns ON transcription in response to a stimulus / condition.

Positive repressible operon:

An activator protein is inactivated in response to a stimulus / condition, turning transcription OFF.

Negative inducible operon:

An repressor protein is inactivated in response to a stimulus / condition, turning transcription turns ON.

Negative repressible operon:

An repressor protein turns transcription turns OFF in response to a stimulus / condition.

Basic lac Operon structure

E. coli encounters many different sugars in its environment. These sugars, such as lactose and glucose, require different enzymes for their metabolism. Three of the enzymes for lactose metabolism are grouped in the lac operon: lacZ, lacY, and lacA. LacZ encodes an enzyme called β-galactosidase, which digests lactose into its two constituent sugars: glucose and galactose. lacY is a permease that helps to transfer lactose into the cell. Finally, lacA is a trans-acetylase; the relevance of which in lactose metabolism is not entirely clear. Transcription of the lac operon normally occurs only when lactose is available for it to digest. Presumably, this avoids wasting energy in the synthesis of enzymes for which no substrate is present. A single mRNA transcript includes all three enzyme-coding sequences and is called polycistronic. A cistron is equivalent to a gene.

Cis- and trans- Regulators

In addition to the three protein-coding genes, the lac operon contains short DNA sequences that do not encode proteins, but are instead binding sites for proteins involved in transcriptional regulation of the operon. In the lac operon, these sequences are called P (promoter), O (operator), and CBS (CAP-binding site). Collectively, sequence elements such as these are called cis-elements because they must be located on the same piece of DNA as the genes they regulate. On the other hand, the proteins that bind to these cis-elements are called trans-regulators because (as diffusible molecules) they do not necessarily need to be encoded on the same piece of DNA as the genes they regulate.

LacI is an allosterically regulated repressor

One of the major trans-regulators of the lac operon is encoded by lacI. Four identical molecules of lacI proteins, encoded by a gene distinct from the operon that encodes lacZ, lacY, and lacA, assemble together to form a homotetramer called a repressor. This repressor binds to two operator sequences adjacent to the promoter of the lac operon. Binding of the repressor prevents RNA polymerase from binding to the promoter. Therefore, the operon will not be transcribed when the operator is occupied by a repressor.

Besides its ability to bind to specific DNA sequences at the operator, another important property of the lacI protein is its ability to bind to lactose. When lactose is bound to lacI, the shape of the protein changes in a way that prevents it from binding to the operator. Therefore, in the presence of lactose, RNA polymerase is able to bind to the promoter and transcribe the lac operon, leading to a moderate level of expression of the lacZ, lacY, and lacA genes. Proteins such as lacI that change their shape and functional properties after binding to a ligand are said to be regulated through an allosteric mechanism.

CAP is an allosteric activator of the lac operon

A second aspect of lac operon regulation is conferred by a trans-factor called cAMP binding protein (CAP). CAP is another example of an allosterically regulated trans-factor. Only when the CAP protein is bound to cAMP can another part of the protein bind to a specific cis-element within the lac promoter called the CAP binding sequence (CBS). CBS is located very close to the promoter (P). When CAP is bound to at CBS, RNA polymerase is better able to bind to the promoter and initiate transcription. Thus, the presence of cAMP ultimately leads to a further increase in lac operon transcription.

Figure (PageIndex{3}): CAP, when bound to cAMP, helps RNApol to bind to the lac operon. cAMP is produced only when glucose [Glc] is low. (Origianl-Deyholos-CC:AN)

The physiological significance of regulation by cAMP becomes more obvious in the context of the following information. The concentration of cAMP is inversely proportional to the abundance of glucose: when glucose concentrations are low, an enzyme called adenylate cyclase is able to produce cAMP from ATP. Evidently, E. coli prefers glucose over lactose, and so expresses the lac operon at high levels only when glucose is absent and lactose is present. This provides another layer of logical control of lac operon expression: only in the presence of lactose, and in the absence of glucose is the operon expressed at its highest levels.


6.1: Prokaryotic gene regulation - Biology

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Gene Regulation

Each cell expresses, or turns on, only a fraction of its genes. “Expresses” or “turns on” means that protein is being produced from that gene. The rest of the genes are repressed, or turned off (no protein is being produced from those genes). The process of turning genes on and off is known as gene regulation. Gene regulation is an important part of normal development. Genes are turned on and off in different patterns during development to make a brain cell look and act different from a liver cell or a muscle cell, for example. Gene regulation also allows cells to react quickly to changes in their environments. Although we know that the regulation of genes is critical for life, this complex process is not yet fully understood.

For a cell to function properly, necessary proteins must be synthesized at the proper time. All organisms and cells control or regulate the transcription and translation of their DNA into protein. The process of turning on a gene to produce RNA and protein is called gene expression. Whether in a simple unicellular organism or in a complex multicellular organism, each cell controls when and how its genes are expressed. For this to occur, there must be a mechanism to control when a gene is expressed to make RNA and protein, how much of the protein is made, and when it is time to stop making that protein because it is no longer needed.

Cells in multicellular organisms are specialized cells in different tissues look very different and perform different functions. For example, a muscle cell is very different from a liver cell, which is very different from a skin cell. These differences are a consequence of the expression of different sets of genes in each of these cells. All cells have certain basic functions they must perform for themselves, such as converting the energy in sugar molecules into energy in ATP. Therefore, there is a set of “housekeeping” genes that are expressed in all cells. Each type of cell also has many genes that are not expressed because the cell does not need to perform those functions. Specific cells also express many genes that are not expressed by other cells so that they can carry out their specialized functions. In addition, cells will turn on or off certain genes at different times in response to changes in the environment or at different times during the development of the organism. Unicellular organisms, both eukaryotic and prokaryotic, also turn on and off genes in response to the demands of their environment so that they can respond to special conditions.

Figure 1 The unique color pattern of this cat’s fur is caused by either the orange or the black allele of a gene being randomly silenced (turned off).

The control of gene expression is extremely complex. Malfunctions in this process are detrimental to the cell and can lead to the development of many diseases, including cancer.


Evolution Connection

Alternative RNA Splicing

In the 1970s, genes were first observed that exhibited alternative RNA splicing . Alternative RNA splicing is a mechanism that allows different protein products to be produced from one gene when different combinations of introns (and sometimes exons) are removed from the transcript (Figure 2). This alternative splicing can be haphazard, but more often it is controlled and acts as a mechanism of gene regulation, with the frequency of different splicing alternatives controlled by the cell as a way to control the production of different protein products in different cells, or at different stages of development. Alternative splicing is now understood to be a common mechanism of gene regulation in eukaryotes according to one estimate, 70% of genes in humans are expressed as multiple proteins through alternative splicing.

Figure 2: There are five basic modes of alternative splicing. Segments of pre-mRNA with exons shown in blue, red, orange, and pink can be spliced to produce a variety of new mature mRNA segments.

How could alternative splicing evolve? Introns have a beginning and ending recognition sequence, and it is easy to imagine the failure of the splicing mechanism to identify the end of an intron and find the end of the next intron, thus removing two introns and the intervening exon. In fact, there are mechanisms in place to prevent such exon skipping, but mutations are likely to lead to their failure. Such “mistakes” would more than likely produce a nonfunctional protein. Indeed, the cause of many genetic diseases is alternative splicing rather than mutations in a sequence. However, alternative splicing would create a protein variant without the loss of the original protein, opening up possibilities for adaptation of the new variant to new functions. Gene duplication has played an important role in the evolution of new functions in a similar way—by providing genes that may evolve without eliminating the original functional protein.


Post-translation regulation

Chemical Modifications

Proteins can be chemically modified with the addition of groups including methyl, phosphate, acetyl, and ubiquitin groups.

The addition or removal of these groups from proteins can have many affects and be in response to many cellular changes. For example:

  • Covalent modifications can regulate protein activity.
  • Sometimes these modifications can regulate where a protein is found in the cell - for example, in the nucleus, in the cytoplasm, or attached to the plasma membrane.
  • Chemical modifications occur in response to external stimuli such as stress, the lack of nutrients, heat, or ultraviolet light exposure.
  • These changes can alter epigenetic accessibility, transcription, mRNA stability, or translation - all resulting in changes in expression of various genes.

This is an efficient way for the cell to rapidly change the levels of specific proteins in response to the environment. Because proteins are involved in every stage of gene regulation, the phosphorylation of a protein (depending on the protein that is modified) can alter accessibility to the chromosome, can alter translation (by altering transcription factor binding or function), can change nuclear shuttling (by influencing modifications to the nuclear pore complex), can alter RNA stability (by binding or not binding to the RNA to regulate its stability), can modify translation (increase or decrease), or can change post-translational modifications (add or remove phosphates or other chemical modifications).

Protein degradation

The addition of an ubiquitin group to a protein marks that protein for degradation. Ubiquitin acts like a flag indicating that the protein lifespan is complete. These proteins are moved to the proteasome, an organelle that functions to remove proteins, to be degraded. One way to control gene expression, therefore, is to alter the longevity of the protein (Figure 12.6).


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Describe how transcription in prokaryotic cells can be altered by external stimulation such as excess lactose in the environment.

Environmental stimuli can increase or induce transcription in prokaryotic cells. In this example, lactose in the environment will induce the transcription of the lac operon, but only if glucose is not available in the environment.

What is the difference between a repressible and an inducible operon?

A repressible operon uses a protein bound to the promoter region of a gene to keep the gene repressed or silent. This repressor must be actively removed in order to transcribe the gene. An inducible operon is either activated or repressed depending on the needs of the cell and what is available in the local environment.


Inheritance: Regulation of Gene Expression in Prokaryotes and Eukaryotes

Inheritance

Clever mechanisms turn genes off and on so that they only function when there is a need for their services.

Prokaryotes and the Operon Model

Prokaryotes are sensitive to their environment, and their genetic activity is controlled by specific proteins that interact directly with their DNA to quickly adjust to environmental changes. Genetic expression is the process where genotypes coded in the genes are exhibited by the phenotypes of the individuals. The DNA is copied by the RNA and then synthesized into protein. The process of transcription, which is the synthesis of RNA from a DNA template, is where the regulation of the gene expression is most likely to occur. The default setting for prokaryotes appears to allow for the continual synthesis of protein to occur, whereas in eukaryotes the system is normally off until activated.

An operon is a self-regulating series of genes that work in concert. An operon includes a special segment of genes that are regulators of the protein synthesis, but do not code for protein, called the promoter and operator. These segments overlap, and their interaction determines whether the process will start and when it will stop. RNA polymerase must create RNA by moving along the chromosome and ?reading? the genes in the process of transcription.

RNA polymerase first attaches to the promoter segment, which signals the beginning of a particular DNA sequence. If not blocked, it passes over the operator and reaches the protein-producing genes where it creates the mRNA that instructs the ribosomes to create the desired protein. This process continues until the system is blocked by repressor proteins. Repressors bind with the operator and prevent RNA polymerase from proceeding to create mRNA by prohibiting access to the remainder of the protein-producing genes. As long as the repressor is binding with the operator, no proteins are made. However, when an inducer is present, it binds with the repressor, causing the repressor to change shape and release from the operator. When this happens, the RNA polymerase can proceed with transcription, and protein synthesis begins and continues until another repressor binds with the operator. Refer to the illustration Transcription regulation.

The lac operon model is probably the most studied and well known. In bacteria, such as E. coli, three genes are part of an operon that code for three separate enzymes needed for the breakdown of lactose, a simple sugar. A regulatory gene, located before the operon, continually makes repressor proteins that bind with the operator and prohibit the function of RNA polymerase. The system therefore remains off until a flood of lactose molecules binds with all available repressors and prevents their attachment to the operator. When the operator is free, the production of the enzyme to break down lactose continues until enough of the lactose molecules are broken down to then release repressors to recombine with the operator to stop production of the enzymes.

Two additional types of operons exist that operate in the same way except for the function of the operator. The trp operon differs because the repressor is active only when bonded to a specific molecule. For the remainder of the time, it remains unbonded and inactive in the absence of that molecule. Finally, in a positive twist, activators are used by a third type of operon to bond directly with the DNA, which allows the RNA polymerase to work more efficiently. Absent the activators, RNA polymerase proceeds at a slow rate.

Eukaryotes: Multiple Models of Gene Regulation

Unlike prokaryotes, multiple gene-regulating mechanisms operate in the nucleus before and after RNA transcription, and in the cytoplasm both before and after translation.

Histones are small proteins packed inside the molecular structure of the DNA double helix. Tight histone packing prevents RNA polymerase from contacting and transcribing the DNA. This type of overall control of protein synthesis is regulated by genes that control the packing density of histones. X-chromosome inactivation occurs when dense packing of the X chromosome in females totally prevents its function even in interphase. This type of inactivation is inherited and begins during embryonic development, where one of the X chromosomes is randomly packed, making it inactive for life.

Activator-enhancer complex is unique in eukaryotes because they normally have to be activated to begin protein synthesis, which requires the use of transcription factors and RNA polymerase. In general, the process of eukaryotic protein synthesis involves four steps:

  1. Activators, a special type of transcription factor, bind to enhancers, which are discrete DNA units located at varying points along the chromosome.
  2. The activator-enhancer complex bends the DNA molecule so that additional transcription factors have better access to bonding sites on the operator.
  3. The bonding of additional transcription factors to the operator allows greater access by the RNA polymerase, which then begins the process of transcription.
  4. Silencers are a type of repressor protein that blocks transcription at this point by bonding with particular DNA nucleotide sequences.

The processing and packaging of RNA both in the nucleus and cytoplasm provides two more opportunities for gene regulation to occur after transcription but before translation.

Adding extra nucleotides as a protective cap and tail to the RNA identifies the RNA as an mRNA by the ribosomes, and prevents degradation by cell enzymes as it moves from the nucleus into the cytoplasm.

RNA splicing occurs when ?gaps? of nonprotein-code-carrying nucleotides called interons are removed from the code-carrying nucleotides, called exons, which are then connected to shorten the RNA molecule for conversion into tRNA and rRNA. The number of interons regulates the speed at which the RNA can be processed.

After the extra nucleotides have been added as a cap and tail and the RNA has been spliced, it moves to the cytoplasm where additional mechanisms of gene regulation exist.

The longevity of the individual mRNA molecule determines how many times it can be used and reused to create proteins. In eukaryotes, the mRNA tends to be stable, which means it can be used multiple times which is efficient, but it prevents eukaryotes from making rapid response changes to environmental disruptions. The mRNA of prokaryotes is unstable, allowing for the creation of new mRNA, which has more opportunities to adjust for changing environmental conditions.

Inhibitory proteins prevent the translation of mRNA. They are made inactive when bonded with the substance for which they are trying to block production.

Post-translation control involves the selective cutting and breakdown of proteins that prevent the formation of the final product. In both cases, the hormone or enzyme required to finish or activate the final product may be rendered inactive.

Although much has been learned about inheritance since Mendel's time, the fundamentals remain the same. In sexual reproduction the offspring inherit one half of their genes from the father and one half from the mother. The chance of inheriting a particular gene can be estimated by pedigrees and Punnet squares. Every trait, feature, or characteristic is controlled by genes or a combination of genes. Numerous gene-regulating mechanisms activate and inactivate organism functions.


Biology

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6.1: Prokaryotic gene regulation - Biology

Control of Gene Expression in Prokaryotes

Introduction
Gene expressions are strictly controlled at many levels to ensure the organism having the appropriate response to its environment or internal changes. This is important for prokaryotes because there are usually single-cell organisms, and they largely depend on their environment for all of their activities.

Transcription in bacteria
In bacteria transcription often occur as polycistrons, i.e., many functional-related genes are clustered and transcribed under the same types of regulation. These are called operons. An operon usually contains regulatory genes and structure genes. The gene expression can be induced under certain circumstances or be constitutive.

Lac operon
Lac operon are activated by lactose, which binds to Lac I, a Repressor, and removes it from the operator sequence, and therefore release the repression from Lac I, the consequence is that the structure genes lac Z. lac Y and Lac A are expressed, and the cells are able to use lactose as carbon source.

Trp operon
Similar to Lac operon, Trp operon has TrpR repressor for normal repression of the operon. But in contrary to lac operon, TrpR is normally inactivate, only in the presence of large amount of Trp, TrpR is activated and the trp operon is suppressed. Trp operon also has an attenuator sequence located within the operon to enable the operon sense the decrease or increase of the trp in the environment.

Gene expression in Bacteriophage
When l phage switch between lysogeny and lytic cycles, two repressors play critical roles: cI and Cro. cI encodes Lambda repressor. Cro encode a protein that controls the repressor (and other genes). When cI proteins predominate, phage remains in the lysogenic state When Cro proteins predominate, phage enters the lytic state. The regulation on cI and Cro is very artistic and delicate.

Gene expressions are strictly controlled at many levels to ensure the organism having the appropriate response to its environment or internal changes. In bacteria many functional-related genes are clustered and transcribed under the same types of regulation (operons). An operon usually contains regulatory genes and structure genes. The most studied operons in bacteria are Lac operons and Trp operons, in both of which cases the activation or inactivation of repressors play key roles in gene regulation. This is also true in l phage in terms of regulating its lytic and lysogenic cycles: When cI proteins predominate, phage remains in the lysogenic state When Cro proteins predominate, phage enters the lytic state.

  • Concept map to depict the gene regulation in prokaryotes.
  • Detailed step by step illustration of lac operons
  • Detailed illustration of Trp operon and its attenuator
  • Diagrammatic illustration of l phage gene regulation on cI and Cro
  • Concise key concept sheets

Gene regulation in prokaryotes

  • Introduction
  • Transcription in bacteria
  • Operons
  • Trans and cis-acting elements
  • Inducible and constitutive expression
  • Repressor vs activator

Gene expression in l phage

  • Life cycle of l phage
  • The phage switch: cI and Cro
  • Establish lysogenic cycle
  • Induction of lytic cycle

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Watch the video: Gene Regulation and the Order of the Operon (May 2022).