Untangling the string
By Emily Pritchard, MRC Human Genetics Unit, University of Edinburgh
Human DNA is long, really really long. 2m long, in fact. 2m of this string-like polymer is found the nucleus of every human cell. The thing is, human cell nuclei are pretty tiny, only 20μm in diameter (that’s only 1/50th of a millimetre). This means that that 2m of string is tangled and knotted up into nuclei so small, that over 100,000 of them can fit into the eye of a needle.
On that 2m of DNA are 20,000 genes; they all need to be switched on and off at different times and at different levels (like turning a dimmer switch up and down). But DNA doesn’t just contain genes. Some of it has special sequences to control the genes, changing the level of the dimmer switch. Some of it contains parasitic sequences, often derived from viruses, that hijack the cell’s machinery to copy themselves within and between genomes. Some of it is just rubbish, repetitive nonsense that doesn’t do anything. So proteins need to navigate this, find the genes they need and the sequences that will help switch them on. Finding them is like being given a road atlas to the UK and being asked to find Finkleton Street. But nobody’s told you what town Finkleton Street is in, or even what region. Plus they’ve mixed up all the pages of the map, shoved in some extra pages – some of which are just nonsense and others intentional red herrings. And they’ve helpfully removed the index.
Sounds like total chaos. Fortunately DNA is not a tangled ball of string. It’s folded and twisted in a precise way, allowing chunks to come into contact with one another or with specific proteins, keeping high level genes (for that tissue or developmental stage) in areas with lots of activating proteins, and keeping low-level genes, junk DNA and parasites concealed so they’re not switched on by accident. So first the DNA is wound around beads, then curled around and looped together, then held in specific regions of the nucleus. Now you can find Finkleton Street much quicker, you know the region it might be in, what it might have nearby and there’s no rubbish to distract you. However this status is completely dynamic, continually altering to allow different genes to be switched on over time and in response to stimuli.
We know that the spatial organisation of DNA in the nucleus is vital for genes to be controlled correctly. It’s less clear how this organisation occurs, and how this is able to affect specific genes. I’m looking at a set of proteins called cohesins, that are involved in DNA organisation. I’m studying what happens in a cell when cohesins are altered.
It is clear that there are problems when cohesins are altered. Cornelia de Lange Syndrome (CdLS) is a disease caused by mutation of the genes for cohesins. Patients suffer from abnormal arms and faces, behavioural problems, autistic-like learning difficulties, gastrointestinal reflux, seizures, hirsutism, heart defects, vision defects and slow growth. A mixture of seemingly unrelated symptoms, like this, is what we expect when control of gene switches goes awry.
I want to know why altering cohesins leads to such huge problems. I believe that DNA organisation is less tightly controlled in cells of CdLS patients than in healthy cells. This means that genes do not come into contact with the correct DNA sequences or proteins that would normally switch them on and off at the right time. Looking at nuclei down the microscope, I have seen that DNA in CdLS cells is packaged differently to that in healthy cells, especially in regions where we know cohesins bind to DNA. I would like to find out how DNA is held in place by cohesins, and what regions of the genome are affected by it.
Cohesins were a group of proteins that were always known to be important in cell division. Before cells divide, they have to make copies of the DNA, and the copies of DNA are held together by lots of protein rings until the right time. These loops are made of cohesins. When the cell divides, an enzyme chops the cohesin rings, and the two copies of the DNA are allowed to come apart. We think that, as well as holding copies of DNA together after it replicates, cohesin may also hold loops of DNA together, allowing genes to be switched on simultaneously.
I doubt we will cure CdLS. As it doesn’t normally run in families, doctors are unlikely to test for it prenatally, yet the prenatal damage is too severe to be remedied after birth. However our understanding of how cohesin contributes to DNA organisation will provide insight into many other diseases, diseases that we have more possibility of fighting, including cancers. If we can fully appreciate the factors that switch genes on and off, we can better predict the effects of drugs, gene mutation and gene therapy.
The publication of the Human Genome Sequence was supposed to unlock all sorts of mysteries, but in some ways it has created many more. Each cell is carrying this huge mass of information, which somehow needs to be read and processed. For now all we have is a map, but we don’t know how to read it. To read it properly, we must first untangle the string.