Gene Regulation In Mammalian Cell Structure Biology Essay

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Gene regulation, it is the term given to processes that occur on a biological resolution (that is at the molecular cell level) that is in charge of modulation of genetic expression, therefore defining the degree of protein production, cell determination among other factors that are dependent on genetic information. Here gene regulation will be discussed on basis for eukaryotic cells, more specifically on the regulation of mammalian cells and evolutionary advantages they have obtained in relation to prokaryotes, and how eukaryotes regulate their genomes, that allow for the high degree of complexity of mammals.

The first step in genetic regulation occurs during transcription, this is analogous to prokaryotic gene regulation. Gene expression can be regulated by regulatory proteins, they work by acting as repressors, hence reducing or eliminating transcription, or activators, increasing the gene expression therefore increasing transcription. These regulatory proteins are mostly DNA-binding proteins that bind to a recognition site at or near the gene they control {Baker, T. et al. (2007}.

One of the ways on which regulatory proteins regulate gene expression is by blocking, or helping RNA-polymerase bind to DNA (which without a regulatory protein would only bind weakly), this aids because when binding occurs, it spontaneously changes into the open complex and initiates transcription, this gives a low level of constitutive expression (constant level of gene expression) called the basal level {Baker, T. et al. 2007}. Also since the binding of RNA-polymerase is the rate determining step therefore the action of regulatory proteins can greatly increase or decrease rate of reaction for the process of transcription.{ Baker, T. et al. 2007; Alberts et al 2008}. The way in which repressors block the action of RNA-polymerase is by non-competitive binding, therefore the repressor protein binds to an overlapping region of the RNA-polymerase binding site, this site is called an operator, therefore not allowing the enzyme to bind to the gene and eliminating transcription.{ Baker, T. et al. 2007;Berg et al 2007}. The way in which activators help the action of RNA-polymerase is by cooperative binding, on which one surface of the regulatory protein binds to the DNA, and the other surface end interacts more readily with RNA-polymerase therefore simultaneously bringing the enzyme to the promoter, this process is called recruitment { Baker, T. et al. 2007 }.

Promoters can also interact in different ways, in the case where RNA-polymerase binds efficiently without any help forming a stable closed complex, which will not spontaneously undergo transition to the open complex. In this type of interaction, an activator must stimulate the transition from open to closed complex, because this transition is the rate determining step. This type of activators work by causing an allosteric effect, either by binding to the RNA-polymerase or DNA, causing conformational change and stabilising the transition state.

Even though, altering the rate of transcription is one of the most important regulation methods of gene expression, eukaryotic cells are able to regulate their genome expression with some other different methods.

Mammalian Cells also being eukaryotic cells have their genome wrapped by histone proteins to for nucleosomes. The presence of concealed substrates due to the wrapping of the genomes by the histone proteins means that, without the presence of regulatory proteins expression is reduced, since transcription molecules are partially "concealed". DNA-binding proteins are also able to more readily bind, because of the action of enzymes present in the cells that modify histone proteins therefore facilitating bonding to occur, these factors of nucleosomes, among other regulatory processes, are important to obtain the complexity of mammals that with a genome of 20,000 genes, roughly just more than 10000 base pairs than a weed obtain a complexity that suggest that genome size is one part of the complexity, but the regulatory processes allow for a much higher recombination possibilities therefore allowing for the high degree of complexity to occur {reference}.

Some transcription factors, the so called enhancer-binding proteins, regulate the cell by binding to regions of the DNA that are thousands of base pairs away from the gene they control. This process was found by the experiment that consisted on "promoter-bashing"{ref}, which consisted on retiring the enhancer-binding proteins to see if gene expression would still occur. These experiments allowed the discovery that enhancer-binding proteins need promoters to act, that is when the promoters were "bashed" no expression occurred, also that enhancer proteins are bi-directional, this was found by "bashing" the enhancer-protein DNA-binding site and giving it a mirror image "flip", gene expression still occurred hence it being bi-directional, and finally that enhancer proteins are relatively position independent, that is when the enhancer protein binding site was "bashed" and taken to an altogether different position in relation to the gene, gene expression was still apparent, therefore it also being position independent as enhancers can be located upstream, downstream, or even within the gene they control. This binding increases the rate of transcription of the gene {ref}. One possibility, of the way that the protein-enhancer complex regulates the transcription of a gene, thousands of base pairs away is that enhancer-binding proteins besides their ability to bind to DNA, they have sites that are able to bind to transcription factors(TF) assembled at the promoter of the gene. This will then cause the DNA to loop(which is held and stabilized by cohesion, a protein complex that also holds sister chromatids during mitosis and meiosis){ref}.

Another regulatory factor are silencers, they are DNA control regions that just like enhancers share its properties , is able to affect gene expression thousands of base pairs away from the gene they control, they are also bi-directional and relatively position independent. They are also able to bind to TF although this will cause the gene expression to be repressed.

Since enhancers can turn on promoters of genes located thousands of base pairs away, some control exists that prevents an enhancer from inappropriately binding to and activating the promoter of a different gene in the same region of the chromosome, this is possible through the use of insulators. Insulators are stretches of DNA locate between the enhancer and promoter or the silencer and promoter of adjacent genes. Insulators work by preventing a gene from being influenced by the activation/repression of another gene in its vicinity.

The process of insulation can be seen when looking at the enhancer for the promoter for the delta chain gene, of the gamma/delta T-cell receptor for antigen (TRC) which is located near the promoter of the alpha chain of the alpha/beta TRC. The T cell must then differentiate into one or the other, here the insulator acts and prevents the activation of the genes, as the insulator is between both gene promoters.

Insulators in vertebrates work when bound by a protein designated CCCTC binding factor (CTCF) , CCCTC being a nucleotide sequence found in all insulators, CTCF has 11 zinc fingers (each zinc molecule attaches to cysteine and acts as a regulator factor) .Also in mammals, insulation takes part, only the allele for insulin-like growth-factor-2 (IGF2) inherited from the father is active, the one inherited from the mother is not active. This mechanism consists of the mother's allele containing an insulator between the IGF2 promoter and enhancer, the father's allele also contains this allele, but the insulator has been methylated (addition of a methyl group) therefore its conformation has changed, this in turn prevents CTCF from binding to the insulator, therefore the enhancer is now able to enhance the IGF2 promoter from the father, this process is known as imprinting.

In conclusion, cell regulation for mammalian cells allows for the explanation of how our genome, even though being still significantly larger than prokaryotic genomes its size difference should not be able to account for the complexity differences between mammals and prokaryotes. Here regulations allows for an explanation of how genetic regulation, even though analogous with prokaryotes at the transcription regulation, with its more complex processes such as imprinting, use of enhancers and splicing make it possible for specific cell differentiation and degrees of genetic expression that create the diversity found in mammals possible, therefore cell regulation can be seen as one of the main evolutionary advantages that have allowed mammals to become a very successful niche in the world's ecosystem.

Carlos Andres Mariscal Melgar , 1st year Bsc(Hons)Biomedical Science student.