Enlighten Biology Note on Control of Gene Expression.
Gene regulation
Enzymes which are necessary for reactions present in metabolic pathways like respiration are constantly required, and the genes that code for these are called housekeeping genes.
Protein-based hormones (required for the growth and development of an organism or enzymes) are only required by certain cells at certain times to carry out a short-lived response.
They are coded for by tissue-specific genes.
The entire genome of an organism is present in every prokaryotic cell, or eukaryotic cell that contains a nucleus.
This includes genes not required by that cell so the expression of genes and the rate of synthesis of protein products like enzymes and hormones has to be regulated.
Genes can be turned on or off, and the rate of product synthesis increases or decreases depending on demand.
Bacteria can respond to changes in the environment because of gene regulation.
Expressing genes only when the products are needed also prevents vital resources from being wasted.
Gene regulation is fundamentally the same in both prokaryotes and eukaryotes.
However, the stimuli that cause changes in gene expression and the responses produced are more complex in eukaryotes.
Multicellular organisms not only have to respond to changes in the external environment but also the internal environment.
Gene regulation is required for cells to specialize and work in a coordinated way.
There are several different ways in which genes are regulated, categorized by the level at which they operate:
- Transcriptional – genes can be turned on or off
- Post-transcriptional – mRNA can be modified which regulates translation and the types of proteins produced
- Translational – translation can be stopped or started
- Post-translational – proteins can be modified after synthesis which changes their functions.
Transcriptional control
Several mechanisms can affect the transcription of genes.
Chromatin remodelling
As you have already learned, DNA is a very long molecule and has to be wound around proteins called histones in eukaryotic cells, to be packed into the nucleus of a cell.
The resulting DNA/protein complex is called chromatin.
Heterochromatin is tightly wound DNA causing chromosomes to be visible during cell division whereas euchromatin is loosely wound DNA present during interphase.
The transcription of genes is not possible when DNA is tightly wound because RNA polymerase cannot access the genes.
The genes in euchromatin, however, can be freely transcribed.
Protein synthesis does not occur during cell division but during interphase between cell divisions.
This is a simple form of regulation that ensures the proteins necessary for cell division are synthesized in time.
It also prevents the complex and energy-consuming process of protein synthesis from occurring when cells are dividing.
Histone modification
DNA coils around histones because they are positively charged and DNA is negatively charged.
Histones can be modified to increase or decrease the degree of packing (or condensation).
The addition of acetyl groups (acetylation) or phosphate groups (phosphorylation) reduces the positive charge on the histones (making them more negative) and this causes DNA to coil-less tightly, allowing certain genes to be transcribed.
The addition of methyl groups (methylation) makes the histones more hydrophobic so they bind more tightly to each other causing DNA to coil more lightly and preventing transcription of genes.
Epigenetics is a term that is increasingly used to describe this control of gene expression by the modification of DNA.
It is sometimes used to include all of the different ways in which gene expression is regulated.
Lac operon
An operon is a group of genes that are under the control of the same regulatory mechanism and are expressed at the same time.
Operons are far more common in prokaryotes than eukaryotes owing to the smaller and simpler structure of their genomes.
They are also a very efficient way of saving resources because if certain gene products are not needed, then all of the genes involved in their production can be switched off.
Glucose is easier to metabolize and is the preferred respiratory substrate of Escherichia coli and many other bacteria.
If glucose is in short supply, lactose can be used as a respiratory substrate.
Different enzymes are needed to metabolize lactose.
The lac operon is a group of three genes, lacZ, lacY, and lacA, involved in the metabolism of lactose.
They are structural genes as they code for three enzymes (P-galactosidase, lactose permease, and transacetylase) and they are transcribed onto a single long molecule of mRNA.
A regulatory gene, lack is located near the operon and codes for a repressor protein that prevents the transcription of the structural genes in the absence of lactose.
The repressor protein is constantly produced and binds to an area called the operator, which is also close to the structural genes.
The binding of this protein prevents RNA polymerase from binding to DNA and beginning transcription.
This is called down-regulation.
The section of DNA that is the binding site for RNA polymerase is called the promoter.
When lactose is present, it binds to the repressor protein causing it to change shape so it can no longer bind to the operator.
As a result, RNA polymerase can bind to the promoter, the three structural genes are transcribed, and the enzymes are synthesized.
Role of cyclic AMP
The binding of RNA polymerase still only results in a relatively slow rate of transcription that needs to be increased or up-regulated to produce the required quantity of enzymes to metabolize lactose efficiently.
This is achieved by the binding of another protein, cAMP receptor protein (CRP), which is only possible when CRP is bound to cAMP (a secondary messenger that you are already familiar with).
The transport of glucose into an E. coli cell decreases the levels of cAMP, reducing the transcription of the genes responsible for the metabolism of lactose.
If both glucose and lactose are present then it will still be glucose, the preferred respiratory substrate, that is metabolized.
Post-transcriptional/pre-translational control
RNA processing
The product of transcription is a precursor molecule, pre-mRNA.
This is modified forming mature mRNA before it can bind to a ribosome and code for the synthesis of the required protein.
A cap (a modified nucleotide) is added to the 5Z end and a tail (a long chain of adenine nucleotides) is added to the 3Z end.
These both help to stabilize mRNA and delay degradation in the cytoplasm.
The cap also aids the binding of mRNA to ribosomes.
Splicing also occurs where the RNA is cut at specific points – the introns (non-coding DNA) are removed and the exons (coding DNA) arc joined together. Both processes occur within the nucleus.
RNA editing
The nucleotide sequence of some mRNA molecules can also be changed through base addition, deletion, or substitution.
These have the same effect as point mutations and result in the synthesis of different proteins which may have different functions.
This increases the range of proteins that can be produced from a single mRNA molecule or gene.
Translational control
The following mechanisms regulate the process of protein synthesis:
- degradation of mRNA – the more resistant the molecule the longer it will last in the cytoplasm, that is, a greater quantity of protein synthesized.
- binding of inhibitory proteins to mRNA prevents its binding to ribosomes and the synthesis of proteins.
- activation of initiation factors which aid the binding of mRNA to ribosomes (the eggs of many organisms produce large quantities of mRNA which are not required until after fertilization, at which point initiation factors are activated).
Protein kinases
Protein kinases are enzymes that catalyze the addition of phosphate groups to proteins.
The addition of a phosphate group changes the tertiary structure and so the function of a protein.
Many enzymes are activated by phosphorylation.
Protein kinases are therefore important regulators of cell activity.
Protein kinases are themselves often activated by the secondary messenger cAMP.
Post-translational control
Post-translational control involves modifications to the proteins that have been synthesized.
This includes the following:
- addition of non-protein groups such as carbohydrate chains, lipids, or phosphates
- modifying amino acids and the formation of bonds such as disulfide bridges
- folding or shortening of proteins.
- modification by cAMP – for example, in the lac operon cAMP binds to the cAMP receptor protein increasing the rale of transcription of the structural genes.
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