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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.
Stages of gene expression that are regulated
- Modification of DNA;
- Post-transcriptional modification;
- RNA transport;
- mRNA degradation;
- Post-translational modifications;
Modification of DNA
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.
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.
Acetylation of the arms of histones 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.
Regulation of transcription
Transcription of a gene by RNA polymerase can be regulated by at least three types of proteins:
- 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.
- Repressors bind to non-coding sequences on the DNA strand, impeding RNA polymerase's progress along the strand, thus impeding the expression of the gene.
- Activators enhance the interaction between RNA polymerase and a particular promoter, encouraging the expression of the gene.
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).
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.
- 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.
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.
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 acetylateed, 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.
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.
- The reference in real-time PCR webpage with all relevant aspects in real-time qPCR and qRT-PCR
- real-time PCR Applications Workshops, at the TATAA Biocenter Germany
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