Gene regulation

Definitions & Key takeaways

Gene regulation is the process by which a gene's expression is controlled. This control may be either activation or inhibition. Activational gene control occurs when a particular gene is turned on in response to some signal or stimulus. For example, genes that code for insulin production necessary for the body to metabolize sugar will be active (or "turned on") only when blood sugar levels are high.

Inhibitational gene control, on the other hand, happens when a particular gene is turned off in response to some signal or stimulus. For example, genes that code for insulin production will be inactive when blood sugar levels are low.

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Our DNA is like a library - found in the nucleus of our cells - with thousands of books. Some of these books - called genes - are extremely important, because they carry the recipes for every single protein found in the cell.
Some of these proteins are necessary in all the cells - like the cytoskeletal proteins. But other proteins, like neurotransmitters, are necessary only in certain cell types - like neurons.
Gene regulation is what allows the right cells to make the right proteins at the right time. Now, on the molecular level, DNA is made up of two strands of nucleotides, so each gene is just a segment of this nucleotide sequence.
And there are four types of nucleotides: adenine, guanine, thymine, and cytosine - or A, G, T, C. Now, the entire DNA molecule is wrapped around structural proteins called histones that package the DNA into nucleosomes - like when we roll yarn into a ball to keep it compact and organized.
Altogether, the entire yarn with the DNA plus the histones - is called chromatin. The process of decoding the information stored in the DNA is called gene expression - and it includes transcription and translation.
Transcription is where the enzyme RNA polymerase uses the gene as a template to create a molecule that can leave the nucleus.
This molecule is called messenger RNA or mRNA and it has the same nucleotide sequence as the gene, with one tweak: it has uracil nucleotides - or U - instead of thymine.
This message is encoded so that any 3 nucleotide equate a specific codon which codes for an amino acid or is a stop codon which means that the protein is complete.
In translation, specialized proteins in the cytoplasm - called ribosomes - use the mRNA template to create a string of amino acids that make up the protein.
Gene regulation can occur at the level of transcription, post-transcriptional which is between transcription and translation, or translation.
Let’s start with transcriptional regulation - and to understand that let’s start with a deeper dive into transcription. Transcription begins with general transcription factors binding to a unique DNA sequence – called the promoter – just upstream from a gene.
General transcription factors help unwind the DNA helix so that RNA polymerase can transcribe the gene. However, general transcription factors can only bind to the promoter sequence if the DNA is not too tightly packed around the histones.
Usually, genes that the cell uses frequently - like the hemoglobin genes in red blood cells - are packed more loosely and therefore easier to access.
An interesting form of gene regulation, called epigenetics, can also make genes more or less accessible to general transcription factors and RNA polymerase.
Epigenetics refers to chemical modifications that selectively activate or silence certain genes without modifying the nucleotide sequence of the gene.
These changes can occur in the histones, or to the DNA itself. For histones, this usually happens through acetylation - adding an acetyl group to them -, deacetylation - removing it -, or through methylation - addition of a methyl group.
When an enzyme called histone acetylase adds an acetyl group to histones, this decreases their attraction for DNA, so the genes become more easily accessible for RNA polymerase.
On the other hand, if another enzyme called histone deacetylase removes an acetyl group, it has the opposite effect - increases the attraction between DNA and histones, so DNA wraps more tightly around histones, making the genes less accessible.
Methylation, on the other hand can both increase and decrease transcription, depending on how many methyl groups are added.
If only one methyl group is added, this decreases the attraction between the DNA and the histone, so the genes are easily accessible.
If we add two or three methyl groups to it, however, the histone will repress, or lock down, preventing the transcription of those genes.
Epigenetic changes in DNA, on the other hand, are mostly based on methylation - the addition of a methyl group, usually to a cytosine residue, prevents general transcription factors from binding to the promoter, decreasing gene expression.
As it turns out, DNA methylation also stimulates histone deacetylation - so that further inhibits transcription. So let’s say that based on the epigenetic modifications, our gene is exposed and ready to be transcribed.
Sometimes cells need to increase or decrease transcription of a certain gene, and here’s where other types of transcription factors called activators or repressors get involved.
Activators kickstart gene transcription through positive regulation. They bind to a DNA sequence called the enhancer, which is on the same DNA strand as the gene - sometimes it’s near the promoter, but other times it’s further upstream or downstream.
So, if the right stimulus - a ligand - reaches the cell, it gets the activator to move from the cytoplasm into the nucleus, and binds to the enhancer.
Once the activator is bound to the enhancer, it can loop the DNA around in such a way that it makes it even easier for general transcription factors and the RNA polymerase to bind to the promoter region.
In addition, activators help recruit histone acetyltransferases - which also promotes binding of RNA polymerase and transcription.
On the other hand there are repressors which inhibit gene transcription through negative regulation. Repressors bind to a DNA sequence called the silencer, which is also on the same DNA strand as the gene.
When the repressor is inactive, it’s floating freely in the cytoplasm. But when the repressor protein is active, it moves into the nucleus, binds to the silencer sequence, and prevents RNA polymerase from binding to the promoter - thus inhibiting transcription.
Repressors can also recruit histone deacetylases, which also inhibit binding of RNA polymerase and transcription. The thyroid hormone receptor is an interesting example because it can act as a repressor and an activator, depending on the situation.
When there’s no thyroid hormone in the cytoplasm, the thyroid receptor behaves like a repressor. It is bound to another protein called a co-repressor and they bind to the silencer sequence of DNA and they recruit histone deacetylases - inhibiting transcription.
However, once the thyroid hormone enters the cell, it binds to the thyroid receptor, and this induces a conformational change in the receptor - it’s like the receptor has an epiphany, and now it behaves like an activator, releasing the corepressor and binding a coactivator instead.
The receptor and the coactivator then bind to the enhancer region and they recruit histone acetylases - stimulating transcription.
Once a gene is transcribed, we move into post-transcriptional regulation, which includes RNA splicing and processing. The freshly made RNA has the exact same nucleotide sequence as the gene.
However, genes are made up of both coding sequences - which are called exons - and non-coding sequences - which are called introns.
So RNA has to be spliced - meaning a molecular protein complex called a spliceosome comes in, and removes the introns from the RNA molecule, making messenger RNA - or mRNA - a much more efficient message.
Kinda like video editing, when you cut bits of the raw footage for a much cleaner final cut. Something interesting can happen here, which is called alternative splicing.
For example, let’s say there’s an RNA strand like this: exon 1 – intron 1 – exon 2 – intron 2 – exon 3. Depending on which proteins the cell needs to make, the spliceosome might do a few different things.
It might just result in one, two, or three of the exons as separate pieces of RNA - each going on to make a protein. Or it could cut out all the sequence from the start of intron 1 to the end of intron 2 – thus taking exon 2 along.
In this case only 2 proteins will be synthesised, the products of exon 1 and exon 3. Ultimately, once all of the post-transcriptional changes are made to the RNA, the resulting RNA sequence is now called messenger RNA - or mRNA for short.
However, it’s dangerous for mRNA to exit the nucleus like this, because lurking in the cytoplasm there are enzymes called exonucleases.
Exonucleases really like cleaving nucleotides off the mRNA ends - and remember, they all code for amino acids now. So mRNA undergoes processing - meaning, it gets a cap and a nice poly-A tail.
Capping basically means RNA gets a protective 7-methyl-guanine molecule at its 5’ end. The poly-A tail at the 3’ end is a long sequence of only adenine nucleotides - usually over 250 of them.
In a nutshell, with a nice cap and a long poly-A tail, mRNA has a longer lifespan - so more proteins can be made using the same RNA molecule.
Now, rarely, another form of post-transcriptional regulation can occur, called RNA editing. This is where specific enzymes change the coding sequence by insertion, deletion or substitution of nucleotides into the mRNA strand.
These are called adenosine or cytosine deaminase acting on RNA enzymes - or ADAR and CDAR for short. ADAR converts the nucleotide adenosine to inosine, while CDAR converts the nucleotide cytosine to uracil.
An example is apolipoprotein B, which is a protein that helps carry lipids in the blood. In the liver, the mRNA is fully translated into the protein apo B-100.
In the intestine, the same mRNA undergoes a change. A CDAR changes the cytosine in the codon CAA - which codes for an amino acid - to an uracil, resulting in a UAA stop codon - that stops translation.
As a result, the translated protein is a smaller variant called apo B-48. So, RNA editing helps determine where specific types of lipoprotein are synthesized.
So after splicing, processing and, occasionally, editing, mRNA is finally safe in the cytoplasm, ready to be translated by a ribosome into a protein.
The ribosome has two subunits, called 40S and 60S, which work together to translate mRNA into a protein. Translation is divided into three main stages.
There’s initiation which is where the 40S subunit of the ribosome recognizes the start codon and summons the 60S subunit to begin translating.
There’s elongation which is where both subunits translate the codons into an amino acid sequence that makes up the primary structure of the protein.
Finally, there’s termination which is where the ribosome recognizes a stop codon as a signal for 40s and 60s subunits to separate and release the protein.
Translational regulation mainly happens during initiation. Normally, regulatory proteins called initiation factors have to bind to either the cap or the poly-A tail, before the 40s ribosomal unit can begin translation - they give the final go ahead.
Conditions like starvation or stress inactivate these initiation factors, which shuts down translation at this stage in order to save energy.
Alright, as a quick recap… Gene regulation occurs at specific stages: transcriptional, post-transcriptional, and translational.
Transcriptional regulation includes modification of DNA and regulation through specialized proteins called transcription factors.
Post-transcriptional regulation includes RNA processing - which includes splicing and addition of CAP and poly A tail - as well as RNA editing.
Finally, translational regulation happens mainly when inactivation of initiation factors can prevent the ribosome from translating the mRNA, thus stopping the protein synthesis.