Read The Epigenetics Revolution Online
Authors: Nessa Carey
Tags: #Science/Life Sciences/Genetics and Genomics
The Epigenetics Revolution (8 page)
The three billion base-pairs we inherit from each parent aren’t formed of one long string of DNA. They are arranged into smaller bundles, which are the chromosomes. We’ll delve deeper into these in
Chapter 9
.
Chapter 9
.
Reading the script
Let’s go back to the more fundamental question of what these six billion base-pairs of DNA actually do, and how the script works. More specifically how can a code that only has four letters (A, C, G and T) create the thousands and thousands of different proteins found in our cells? The answer is surprisingly elegant. It could be described as the modular paradigm of molecular biology but it’s probably far more useful to think of it as Lego.
Lego used to have a great advertising slogan ‘It’s a new toy every day’, and it was very accurate. A large box of Lego contains a limited number of designs, essentially a fairly small range of bricks of certain shapes, sizes and colours. Yet it’s possible to use these bricks to create models of everything from ducks to houses, and from planes to hippos. Proteins are rather like that. The ‘bricks’ in proteins are quite small molecules called amino acids, and there are twenty standard amino acids (different Lego bricks) in our cells. But these twenty amino acids can be joined together in an incredible array of combinations of all sorts of diversity and length, to create an enormous number of proteins.
That still leaves the problem of how even as few as twenty amino acids can be encoded by just four bases in DNA. The way this works is that the cell machinery ‘reads’ DNA in blocks of three base-pairs at a time. Each block of three is known as a codon and may be AAA, or GCG or any other combination of A, C, G and T. From just four bases it’s possible to create sixty-four different codons, more than enough for the twenty amino acids. Some amino acids are coded for by more than one codon. For example, the amino acid called lysine is coded for by AAA and AAG. A few codons don’t code for amino acids at all. Instead they act as signals to tell the cellular machinery that it’s at the end of a protein-coding sequence. These are referred to as stop codons.
How exactly does the DNA in our chromosomes act as a script for producing proteins? It does it through an intermediary protein, a molecule called messenger RNA (mRNA). mRNA is very like DNA although it does differ in a few significant details. Its backbone is slightly different from DNA (hence RNA, which stands for ribonucleic acid rather than deoxyribonucleic acid); it is single-stranded (only one backbone); it replaces the T base with a very similar but slightly different one called U (we don’t need to go into the reason it does this here). When a particular DNA stretch is ‘read’ so that a protein can be produced using that bit of script, a huge complex of proteins unzips the right piece of DNA and makes mRNA copies. The complex uses the base-pairing principle to make perfect mRNA copies. The mRNA molecules are then used as temporary templates at specialised structures in the cell that produce protein. These read the three letter codon code and stitch together the right amino acids to form the longer protein chains. There is of course a lot more to it than all this, but that’s probably sufficient detail.
An analogy from everyday life may be useful here. The process of moving from DNA to mRNA to protein is a bit like controlling an image from a digital photograph. Let’s say we take a photograph on a digital camera of the most amazing thing in the world. We want other people to have access to the image, but we don’t want them to be able to change the original in any way. The raw data file from the camera is like the DNA blueprint. We copy it into another format, that can’t be changed very much – a PDF maybe – and then we email out thousands of copies of this PDF, to everyone who asks for it. The PDF is the messenger RNA. If people want to, they can print paper copies from this PDF, as many as they want, and these paper copies are the proteins. So everyone in the world can print the image, but there is only one original file.
Why so complicated, why not just have a direct mechanism? There are a number of good reasons that evolution has favoured this indirect method. One of them is to prevent damage to the script, the original image file. When DNA is unzipped it is relatively susceptible to damage and that’s something that cells have evolved to avoid. The indirect way in which DNA codes for proteins minimises the period of time for which a particular stretch of DNA is open and vulnerable. The other reason this indirect method has been favoured by evolution is that it allows a lot of control over the amount of a specific protein that’s produced, and this creates flexibility.
Consider the protein called alcohol dehydrogenase (ADH). This is produced in the liver and breaks down alcohol. If we drink a lot of alcohol, the cells of our livers will increase the amounts of ADH they produce. If we don’t drink for a while, the liver will produce less of this protein. This is one of the reasons why people who drink frequently are better able to tolerate the immediate effects of alcohol than those who rarely drink, who will become tipsy very quickly on just a couple of glasses of wine. The more often we drink alcohol, the more ADH protein our livers produce (up to a limit). The cells of the liver don’t do this by increasing the number of copies of the
ADH
gene. They do this by reading the
ADH
gene more efficiently, i.e. producing more mRNA copies and/or by using these mRNA copies more efficiently as protein templates.
ADH
gene. They do this by reading the
ADH
gene more efficiently, i.e. producing more mRNA copies and/or by using these mRNA copies more efficiently as protein templates.
As we shall see, epigenetics is one of the mechanisms a cell uses to control the amount of a particular protein that is produced, especially by controlling how many mRNA copies are made from the original template.
The last few paragraphs have all been about how genes encode proteins. How many genes are there in our cells? This seems like a simple question but oddly enough there is no agreed figure on this. This is because scientists can’t agree on how to define a gene. It used to be quite straightforward – a gene was a stretch of DNA that encoded a protein. We now know that this is far too simplistic. However, it’s certainly true to say that all proteins are encoded by genes, even if not all genes encode proteins. There are about 20,000 to 24,000 protein-encoding genes in our DNA, a much lower estimate than the 100,000 that scientists thought was a good guess just ten years ago
1
.
1
.
Editing the script
Most genes in human cells have quite a similar structure. There’s a region at the beginning called the promoter, which binds the protein complexes that copy the DNA to form mRNA. The protein complexes move along through what’s known as the body of the gene, making a long mRNA strand, until they finally fall off at the end of the gene.
Imagine a gene body that is 3,000 base-pairs long, a perfectly sensible length for a gene. The mRNA will also be 3,000 base-pairs long. Each amino acid is encoded by a codon composed of three bases, so we would predict that this mRNA will encode a protein that is 1,000 amino acids long. But, perhaps unexpectedly, what we find is that the protein is usually considerably shorter than this.
If the sequence of a gene is typed out it looks like a long string of combinations of the letters A, C, G and T. But if we analyse this with the right software, we find that we can divide that long string into two types of sequences. The first type is called an exon (for
ex
pressed sequence) and an exon can code for a run of amino acids. The second type is called an intron (for
in
expressed sequence). This doesn’t code for a run of amino acids. Instead it contains lots of the ‘stop’ codons that signal that the protein should come to an end.
ex
pressed sequence) and an exon can code for a run of amino acids. The second type is called an intron (for
in
expressed sequence). This doesn’t code for a run of amino acids. Instead it contains lots of the ‘stop’ codons that signal that the protein should come to an end.
When the mRNA is first copied from the DNA it contains the whole run of exons and introns. Once this long RNA molecule has been created, another multi-sub-unit protein complex comes along. It removes all the intron sequences and then joins up the exons to create an mRNA that codes for a continuous run of amino acids. This editing process is called splicing.
This again seems extremely complicated, but there’s a very good reason that this complex mechanism has been favoured by evolution. It’s because it enables a cell to use a relatively small number of genes to create a much bigger number of proteins. The way this works is shown in
Figure 3.3
.
Figure 3.3
.
The initial mRNA contains all the exons and all the introns. Then it’s spliced to remove the introns. But during this splicing some of the exons may also be removed. Some exons will be retained in the final mRNA, others will be skipped over. The various proteins that this creates may have quite similar functions, or they may differ dramatically. The cell can express different proteins depending on what that cell has to do at a particular time, or because of different signals that it receives. If we define a gene as something that encodes a protein, this mechanism means that just 20,000 or so genes can code for far more than just 20,000 proteins.
Figure 3.3
The DNA molecule is shown at the very top of this diagram. The exons, which code for stretches of amino acids, are shown in the dark boxes. The introns, which don’t code for amino acid sequences, are represented by the white boxes. When the DNA is first copied into RNA, indicated by the first arrow, the RNA contains both the exons and the introns. The cellular machinery then removes some or all of the introns (the process known as splicing). The final messenger RNA molecules can thereby code for a variety of proteins from the same gene, as represented by the various words shown in the diagram. For simplicity, all the introns and exons have been drawn as the same size, but in reality they can vary widely.
The DNA molecule is shown at the very top of this diagram. The exons, which code for stretches of amino acids, are shown in the dark boxes. The introns, which don’t code for amino acid sequences, are represented by the white boxes. When the DNA is first copied into RNA, indicated by the first arrow, the RNA contains both the exons and the introns. The cellular machinery then removes some or all of the introns (the process known as splicing). The final messenger RNA molecules can thereby code for a variety of proteins from the same gene, as represented by the various words shown in the diagram. For simplicity, all the introns and exons have been drawn as the same size, but in reality they can vary widely.
Whenever we describe the genome we talk about it in very two-dimensional terms, almost like a railway track. Peter Fraser’s laboratory at the Babraham Institute outside Cambridge has published some extraordinary work showing it’s probably nothing like this at all. He works on the genes that code for the proteins required to make haemoglobin, the pigment in red blood cells that carries oxygen all around the body. There are a number of different proteins needed to create the final pigment, and they lie on different chromosomes. Doctor Fraser has shown that in cells that produce large amounts of haemoglobin, these chromosome regions become floppy and loop out like tentacles sticking out of the body of an octopus. These floppy regions mingle together in a small area of the cell nucleus, waving about until they can find each other. By doing this, there is an increased chance that all the proteins needed to create the functional haemoglobin pigment will be expressed together at the same time
2
.
2
.
Each cell in our body contains 6,000,000,000 base-pairs. About 120,000,000 of these code for proteins. One hundred and twenty million sounds like a lot, but it’s actually only 2 per cent of the total amount. So although we think of proteins as being the most important things our cells produce, about 98 per cent of our genome doesn’t code for protein.
Until recently, the reason that we have so much DNA when so little of it leads to a protein was a complete mystery. In the last ten years we’ve finally started to get a grip on this, and once again it’s connected with regulating gene expression through epigenetic mechanisms. It’s now time to move on to the molecular biology of epigenetics.
The important thing in science is not so much to obtain new facts as to discover new ways of thinking about them.
Sir William Bragg
So far this book has focused mainly on outcomes, the things that we can observe that tell us that epigenetic events happen. But every biological phenomenon has a physical basis and that’s what this chapter is about. The epigenetic outcomes we’ve described are all a result of variations in expression of genes. The cells of the retina express a different set of genes from the cells in the bladder, for example. But how do the different cell types switch different sets of genes on or off?
The specialised cell types in the retina and in the bladder are each at the bottom of one of the troughs in Waddington’s epigenetic landscape. The work of both John Gurdon and Shinya Yamanaka showed us that whatever mechanism cells use for staying in these troughs, it’s not anything to do with changing the DNA blueprint of the cell. That remains intact and unchanged. Therefore keeping specific sets of genes turned on or off must happen through some other mechanism, one that can be maintained for a really long time. We know this must be the case because some cells, like the neurons in our brains, are remarkably long-lived. The neurons in the brain of an 85-year-old person, for example, are about 85 years of age. They formed when the individual was very young, and then stayed the same for the rest of their life.
Other books
Animal Magnetism by Shalvis, Jill
This Could Have Been Our Song!: A coulda woulda shoulda ballad by Ngontang Mba, Danielle-Claude
How To Tame a Rake by Maggi Andersen
The Confessions of Frances Godwin by Robert Hellenga
Paddington Races Ahead by Michael Bond
The New World: A Novel by Chris Adrian, Eli Horowitz
Unhooking the Moon by Gregory Hughes
The Accidental Mistress by Kate Harper
The Spell by Alan Hollinghurst
Sin historial by Lissa D'Angelo
