Gene regulation

From Academic Kids

Gene regulation is the general term for cellular control of protein synthesis at the DNA-RNA transcription step. Since this is the root of the central dogma of biology, gene regulation gives the cell the broadest control over structure and function. The level of broad control, however, comes at the expense of timing; since the effects of any change in gene regulation are far downstream, gene regulation is often used for processes which have relatively long-term effects, in contrast to signal transduction which is how the cell handles events quickly (though often it results in gene regulation). Examples of gene regulation include heat shock proteins generated by the fruit fly Drosophila melanogaster.

Contents

Mechanisms for gene regulation

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 bisulphite 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 sliencing. The combination of the two seems to be a signal for DNA to be packed more densely, lowering gene expression.

Regulation of transcription machinery

In order for a gene to be expressed, several things must happen. Firstly, 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.de:Genregulation

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