Gene expression can be regulated by various cellular processes with the aim to control the amount and nature of the expressed genes. This article aims to describe the regulatory mechanisms that control gene expression in both eukaryotes and prokaryotes.
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Gene expression is controlled with the help of regulatory proteins at numerous levels. These regulatory proteins bind to DNA and send signals that indirectly control the rate of gene expression. The up-regulation of a gene refers to an increase in the expression of a gene whilst down-regulation refers to the decrease in the expression of a gene.
The regulation of gene expression is more complex in eukaryotes than in prokaryotes. This is because of the presence of a nuclear membrane in eukaryotes which separates the genetic material from the translation machinery.
This necessitates some additional steps such as messenger RNA (mRNA) transport and resultant eukaryotic gene regulation at many different points. In contrast, prokaryotes lack a clearly defined nucleus hence the key point at which their gene regulation occurs is during transcriptional initiation.
What are promoters and enhancers?
Promoters are specific sequences present upstream to the coding sequence where the RNA Pol is able to bind. There are three sequence elements in bacterial promoters, while eukaryotes can have up to seven sequence elements. The prokaryotes have the Pribnow box (also termed Pribnow-Schaller box) that consists of the “TATAAT” sequence which acts as the region of initiation.
This sequence is present about ten base pairs away from the region where the transcription is initiated. Although this exact sequence may not be present in all Pribnow boxes, this is the most common sequence present. Apart from the Pribnow box, in many cases, an additional sequence of TTGCA is also present about 35 bases upstream of the gene sequence. This is an ‘AT-rich region’ that is known to enhance the transcription rate.
In eukaryotes, the promoters have more complexity. This is partly because there are three classes of RNA pol in eukaryotes – In contrast to one in prokaryotes. Moreover, for eukaryotic genes, there may be an additional class of enhancer sequences.
These sequences can be present at comparatively larger distances away from the coding regions. They have the capacity to alter the gene activation even from a distance by binding to respective activator proteins. This can change the three-dimensional structure of DNA, which in turn can “attract” RNA Pol II.
Eukaryotes have a “TATA” box that is present 25–35 bases upstream to the region where the transcription is initiated. Depending on their effect on transcription rata and gene expression, promoters and enhancers are further classified as “weak” and “strong”.
Regulating Gene Expression
In eukaryotes, the expression of biologically active proteins can be modulated at several points as follows:
Eukaryotic DNA is compacted into chromatin structures which can be altered by histone modifications. Such modifications can result in the up- or down-regulation of a gene.
Initiation of Transcription
This is a key point of regulation of eukaryotic gene expression. Here, several factors such as promoters and enhancers alter the ability of RNA polymerase to transcribe the mRNA, thus modulating the expression of the gene.
Modifications such as polyadenylation, splicing, and capping of the pre-mRNA transcript in eukaryotes can lead to different levels and patterns of gene expression. For example, different splicing patterns for the same gene will generate biologically different proteins following translation.
After post-transcriptional processing, the mature mRNA must be transported from the nucleus to the cytosol so that it can be translated into a protein. This step is a key point of regulation of gene expression in eukaryotes.
Stability of mRNA
Eukaryotic mRNA differs in their stability and some unstable transcripts usually have sequences that bind to microRNA and reduces the stability of mRNA, resulting in down-regulation of the corresponding proteins.
Initiation of Translation
At this stage, the ability of ribosomes in recognizing the start codon can be modulated, thus affecting the expression of the gene. Several examples of translation initiation at non-AUG codons in eukaryotes are available.
Common modifications in polypeptide chains include glycosylation, fatty acylation, and acetylation - these can help in regulating expression of the gene and offering vast functional diversity.
Protein Transport and Stability
Following translation and processing, proteins must be carried to their site of action in order to be biologically active. Also, by controlling the stability of proteins, the gene expression can be controlled. Stability varies greatly depending on specific amino acid sequences present in the proteins.
Regulation of Gene Expression in Prokaryotes
Prokaryotic genes are clustered into operons, each of which code for a corresponding protein.
In prokaryotes, transcription initiation is the main point of control of gene expression. It is chiefly controlled by 2 DNA sequence elements of size 35 bases and 10 bases, respectively. These elements are called promoter sequences as they help RNA polymerase recognize the start sites of transcription. RNA polymerase recognizes and binds to these promoter sequences.
The interaction of RNA polymerase with promoter sequences is in turn controlled by regulatory proteins called activators or repressors based on whether they positively or negatively affect the recognition of promoter sequence by RNA pol.
There are 2 major modes of transcriptional control in E. coli to modulate gene expression. Both of these control mechanisms involve repressor proteins.
In this system, control is exerted upon operons that produce genes necessary for the energy utilization. The lac operon is an example of this in E. coli.
In E. coli, glucose has a positive effect on the expression of genes that encode enzymes involved in the catabolism of alternative sources of carbon and energy such as lactose. Due to the preference for glucose, in its presence enzymes involved in the catabolism of other energy sources are not expressed. In this way, glucose represses the lac operon even if an inducer (lactose) is present.
This modulates operons necessary for biomolecule synthesis. This is called attenuated operon as the operons are attenuated by specific sequences present in the transcribed RNA – gene expression is therefore dependent on the ability of RNA Polymerase to continue elongation past specific sequences.
An example of an attenuated operon is the trp operon which encodes five enzymes necessary for tryptophan biosynthesis in E.coli. These genes are expressed only when tryptophan synthesis is necessary i.e. when tryptophan is not environmentally present. This is partly controlled when a repressor binds to tryptophan and prevents transcription for unnecessary tryptophan biosynthesis.