Regulation of gene expression
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Gene modulation redirects here. For information on therapeutic regulation of gene expression, see therapeutic gene modulation.
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Regulation of gene expression (gene regulation) is the cellular control of the amount and timing of appearance of the functional product of a gene. Although a functional gene product may be an RNA or a protein, the majority of the known mechanisms regulate the expression of protein coding genes. Any step of gene expression may be modulated, from the DNA-RNA transcription step to post-translational modification of a protein. Gene regulation gives the cell control over structure and function, and is the basis for cellular differentiation, morphogenesis and the versatility and adaptability of any organism.
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[edit] Stages of gene expression that are regulated
Any step of gene expression may be modulated, from the DNA-RNA transcription step to post-translational modification of a protein. Following is a list of stages where gene expression is regulated:
- Chemical and structural modification of DNA or chromatin;
- Transcription;
- Translation;
- Post-transcriptional modification;
- RNA transport;
- mRNA degradation;
- Post-translational modifications;
[edit] Modification of DNA
[edit] Chemical modification of DNA
Methylation of DNA is a common method of gene silencing. DNA is typically methylated by methyltransferase enzymes on cytosine nucleotides in a CpG dinucleotide sequence (also called "CpG islands"). Analysis of the pattern of methylation in a given region of DNA (generally a promoter) can be achieved through a method called bisulfite mapping. Methylated cytosine residues are unchanged by the treatment, whereas unmethylated ones are changed to uracil. The differences are analyzed in sequencing gels. Abnormal methylation patterns are thought to be involved in carcinogenesis.
[edit] Structural modification of DNA
Transcription of DNA is dictated by its structure. In general, the density of its packing is indicative of the frequency of transcription. Octameric protein complexes called histones are responsible for the amount of supercoiling of DNA, and these complexes can be temporarily modified by processes such as phosphorylation or more permanently modified by processes such as methylation. Such modifications are considered to be responsible for more or less permanent changes in gene expression levels.
Histone acetylation is also an important process in transcription. Histone acetyltransferase enzymes (HATs) such as CREB-binding protein also dissociate the DNA from the histone complex, allowing transcription to proceed. Often, DNA methylation and histone acetylation work together in gene silencing. The combination of the two seems to be a signal for DNA to be packed more densely, lowering gene expression.
[edit] Regulation of transcription
Regulation of transcription controls when transcription occurs and how much RNA is created. Transcription of a gene by RNA polymerase can be regulated by at least five mechanisms: (Raven 366-71)
- Specificity factors alter the specificity of RNA polymerase for a given promoter or set of promoters, making it more or less likely to bind to them (i.e. sigma factors used in prokaryotic transcription). (Raven 370)
- Repressors bind to non-coding sequences on the DNA strand that are close to or overlapping the promoter region, impeding RNA polymerase's progress along the strand, thus impeding the expression of the gene. (Raven 367)
- Basal factors These transcription factors position RNA polymerase at the start of a protein-coding sequence and then release the polymerase to transcribe the mRNA. (Raven 370)
- Activators enhance the interaction between RNA polymerase and a particular promoter, encouraging the expression of the gene. Activators do this by increasing the attraction of RNA polymerase for the promoter, through interactions with subunits of the RNA polymerase or indirectly by changing the structure of the DNA. (Raven 369)
- Enhancers are sites on the DNA helix that are bound to by activators in order to loop the DNA bringing a specific promoter to the initiation complex.[1]
[edit] Regulatory protein
Regulatory protein is a term used in genetics to describe a protein involved in regulating gene expression. It is usually bound to a regulatory binding site which is sometimes located near the promotor although this is not always the case. Regulatory proteins is often need to be bound to a regulatory binding site to switch a gene on (activator) or to shut off a gene (repressor). Generally, as the organism grows more sophisticated, their cellular protein regulation becomes more complicated and indeed some human genes can be controlled by many activators and repressors working together.
[edit] Prokaryotes vs. eukaryotes
In prokaryotes regulation of transcription is needed for the cell to quickly adapt to the ever changing outer environment. The presence of the quantity and type of nutrients determines which genes are expressed so in order to do that genes needed to be regulated in some fashion. In prokaryotes, repressors bind to regions called operators that are generally located downstream from and near the promoter (normally part of the transcript). Activators bind to the upstream portion of the promoter, such as the CAP region (completely upstream from the transcript). A combination of activators, repressors and rarely enhancers (in prokaryotes) determines whether a gene is transcribed.[2]
In eukaryotes, transcriptional regulation tends to involve combinatorial interactions between several transcription factors, which allow for a sophisticated response to multiple conditions in the environment. This permits spatial and temporal differences in gene expression. Eukaryotes also make use of enhancers, distant regions of DNA that can loop back to the promoter. A major difference between euakaryotes and prokaryotes is the fact the eukaryotes have a nuclear membrane, which prevents simultaneous transcription and translation. (Choudhuri)
[edit] Examples
Examples:
- When E. coli bacteria are subjected to heat stress, the σ32 subunit of its RNA polymerase changes such that the enzyme binds to a specialized set of promoters that precede genes for heat-shock response proteins.
- When a cell contains a surplus amount of the amino acid tryptophan, the acid binds to a specialized repressor protein (tryptophan repressor). The binding changes the structural conformity of the repressor such that it binds to the operator region for the operon that synthesizes tryptophan, preventing their expression and thus suspending production. This is a form of negative feedback.
- In bacteria, the lac repressor protein blocks the synthesis of enzymes that digest lactose when there is no lactose to feed on. When lactose is present, it binds to the repressor, causing it to detach from the DNA strand.
[edit] Inducible vs. repressible systems
Gene Regulation can be summarized as how they respond:
- Inducible systems - An inducible system is off unless there is the presence of some molecule (called an inducer) that allows for gene expression. The molecule is said to "induce expression". The manner in which this happens is dependent on the control mechanisms as well as differences between prokaryotic and eukaryotic cells.
- Repressible systems - A repressible system is on except in the presence of some molecule (called a corepressor) that suppresses gene expression. The molecule is said to "repress expression". The manner in which this happens is dependent on the control mechanisms as well as differences between prokaryotic and eukaryotic cells.
[edit] Posttranscriptional Regulation
After the DNA is transcribed and mRNA is formed there must be some sort of regulation on how much the mRNA is translated into Proteins. Cells do this by Capping, Splicing, and the addition of a Poly(A) Tail. These processes occur in eukaryotes but not in prokaryotes. (Raven, 374-378)
- Capping changes the five prime end of the mRNA to a three prime end by 5'-5' linkage, which protects the mRNA from 5' exonuclease, which degrades foreign RNA. The cap also helps in ribosomal binding. (Raven 378)
- Splicing removes the introns, noncoding regions that are transcribed into RNA, in order to make the mRNA able to create proteins. Cells do this by spliceosome's binding on either side of an intron, looping the intron into a circle and then cleaving it off. The two ends of the extrons are then joined together. (Raven 378)
- Addition of poly(A) tail a poly(A) tail is just junk RNA added to the 3' end in order to slowly be degraded by a 3' exonuclease in order to increase the half life of mRNA. (Raven, 378)
[edit] Regulation of transcription machinery
In order for a gene to be expressed, several things must happen. First, there needs to be an initiating signal. This is achieved through the binding of some ligand to a receptor. Activation of g-protein-coupled receptors can have this effect; as can the binding of hormones to intra- or extracellular receptors.
This signal gives rise to the activation of a protein called a transcription factor, and recruits other members of the "transcription machine." Transcription factors generally simultaneously bind DNA as well as an RNA polymerase, as well as other agents necessary for the transcription process (HATs, scaffolding proteins, etc.). Transcription factors, and their cofactors, can be regulated through reversible structural alterations such as phosphorylation or inactivated through such mechanisms as proteolysis.
Transcription is initiated at the promoter site, as an increase in the amount of an active transcription factor binds a target DNA sequence. Other proteins, known as "scaffolding proteins" bind other cofactors and hold them in place. DNA sequences far from the point of initiation, known as enhancers, can aid in the assembly of this "transcription machinery." Histone arms are acetylated, and DNA is transcribed into RNA.
Frequently, extracellular signals induce the expression of immediate early genes (IEGs) such as c-fos, c-jun, or AP-1. These are in and of themselves transcription factors or components thereof, and can further influence gene expression.
[edit] Up-regulation and down-regulation
These processes are important in gene regulation, for example via hormones such as insulin (up-regulation) and glucagon (down-regulation).
- Up-regulation occurs when a cell is deficient in some kind of receptors. In this case, more receptors enter or attach to the membrane of the cell and thus the reactivity of the cell is brought back to normal, reestablishing homeostasis.
- Down-regulation occurs when a cell which is overly sensitized with a prolonged/enhanced period of reaction begins to degrade the receptors in order to return to normal.
[edit] Examples of gene regulation
- Enzyme induction is a process in which a molecule (e.g. a drug) induces (i.e. initiates or enhances) the expression of an enzyme.
- The induction of heat shock proteins in the fruit fly Drosophila melanogaster.
- The Lac operon is an interesting example of how gene expression can be regulated.
[edit] References
- ^ Ptashne M. "Gene regulation by proteins acting nearby and at a distance". Nature 322 (6081): 697-701. PMID 3018583.
- ^ Choudhuri, Supratim. "Gene regulation and molecular toxicology." U.S. Food and Drug Administration.
- Raven, Peter H., George B. Johnson, Jonathan B. Losos, and Susan R. Singer.Biology. 7th ed. New York: McGraw-Hill, 2004.
