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Regulation of gene expression
Gene modulation redirects here. For information on therapeutic regulation of gene expression, see therapeutic gene modulation.
Regulation of gene expression (or gene regulation) refers to the cellular control of the amount and timing of changes to the 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 the gene's expression may be modulated, from DNA-RNA transcription to the post-translational modification of a protein. Gene regulation gives the cell control over its structure and function, and is the basis for cellular differentiation, morphogenesis and the versatility and adaptability of any organism.
Regulated stages of gene expression
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" when densely clustered). Analysis of the pattern of methylation in a given region of DNA (which can be 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 by DNA sequencing or by methods developed to quantify SNPs, such as Pyrosequencing (Biotage) or MassArray (Sequenom), measuring the relative amounts of C/T at the CG dinucleotide. Abnormal methylation patterns are thought to be involved in carcinogenesis.
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.
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)
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 are often needed 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.
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; in order to do that, genes must 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.
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 eukaryotes and prokaryotes is the fact the eukaryotes have a nuclear envelope, which prevents simultaneous transcription and translation. RNA interference also regulate gene expression in most eukaryotes, both by epigenetic modification of promoters and by breaking down mRNA.
Inducible vs. repressible systems
Gene Regulation can be summarized as how they respond:
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.
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)
Up-regulation and down-regulation
Up-regulation is a process which occurs within a cell triggered by a signal (originating internal or external to the cell) which results in increased expression of one or more genes and as a result the protein(s) encoded by those genes. Conversely down-regulation is a process resulting in decreased gene and corresponding protein expression.
Examples of gene regulation
|This article is licensed under the GNU Free Documentation License. It uses material from the Wikipedia article "Regulation_of_gene_expression". A list of authors is available in Wikipedia.|