Silencing disease-causing genes

Our long threads of DNA are packed extraordinarily tightly within the nucleus of our cells. To give you an idea of just how tightly packed, the diameter of an average cell in your body is about 100th of a millimetre, but each cell must contain two metres of DNA – that’s 200,000 times longer than the nucleus is wide.

Yet despite this highly constricted space, we know that DNA moves around, changing its position and structure to achieve different outcomes. In fact, we have recently discovered, that it moves around more than we thought it did, stretching out and closing back in an almost accordion-like way.

Our new research suggests this accordion action may be a critical mechanism in how our bodies read our DNA to turn genes on and off. If so, it means we may have found a way that we could eventually influence our DNA to stop disease-causing genes from being turned on.

Our DNA is tightly packaged around proteins called histones, much like a thread is wrapped tightly around a spool. We call this tiny structure a nucleosome and there are millions of these in each cell. It is the nucleosome that organises DNA within the nucleus of the cell, allowing the DNA to be packaged into that very small space.

However, the DNA is also arranged in such a way that allows the DNA sequence of a particular gene to still be accessible to the proteins that need to read it. It is these proteins that trigger the various processes that allow our cells to function, like producing enzymes for example. DNA needs to be accessible to protein readers for our genes to be turned on and off.

Active genes – those genes that are switched on to make their products – are stretched by having their nucleosomes spaced out, making them accessible to the reader proteins. Inactive genes – that are switched off or silenced – have their nucleosomes tightly packed together and are therefore inaccessible to the reader proteins.

This mechanism of switching genes on and off is responsible for creating the hundreds of diverse cell types that make up the human body. Each cell contains an identical sequence of DNA, but what makes a brain cell different from a blood cell, for example, is the repertoire of genes that are switched on and switched off in each unique cell type. This makes the packaging of DNA, and the incredible array of molecules that control it, extremely important.

My colleague and mentor Professor Marnie Blewitt and I have been researching how a gene gets switched off – the process of going from loosely to tightly packed DNA in nucleosomes. What we found was counterintuitive. Instead of going directly from loosely packed to tightly packed nucleosomes, the DNA of an active gene must first become even more loosely packed prior to becoming densely packed and inactive.

We don’t yet know why this occurs, but we think the DNA must be first stretched out to allow access for all the proteins that facilitate the switching-off or silencing process.

A well-known complex of proteins, known as the BAF complex, is able to move the nucleosomes around to make space at the start of genes that are about to be switched off.

When we remove elements of the BAF complex to make it non-functional, the temporary loose spacing of these regions no longer occurs and genes don’t get switched off. This information teaches us that opening up is essential in the process of switching genes off.

Our knowledge of this accordion-like behaviour of DNA is limited to our research on mouse embryonic stem cells during a particular stage of development, but it has allowed us to see the way hundreds of genes get switched off.

The future of our research in this area is now to determine whether this accordion-like DNA relaxation is required every time a gene is silenced, or if it is limited only to the embryonic development stage we’ve observed. We also want to know why it happens.

This research is microscopic and nuanced, and this is what I love about researching epigenetics – the processes of how genes are switched on and off.

The idea that for the human body to function as it does, each cell requires thousands of microscopic molecular motors, making tiny manipulations in the way our unique catalogue of DNA is being read, absolutely fascinates me. It’s more intricate than I, or anyone, can yet comprehend.

Yet the value of understanding this microscopic machinery is potentially far-reaching. If a disease-causing gene could simply be switched off, then this could potentially be an incredibly powerful way to treat genetic diseases.

Take for example an oncogene – a gene that has become inappropriately switched on in a cell and is making that cell cancerous. If the oncogene could be switched off again, we’d have a new way to treat cancer alongside the armoury of toxic drugs used today.

This sounds great, in theory, but it won’t be possible to do this safely unless we fully understand the intricate molecular processes that are required to turn a gene off.

This dream is a long way off, but our ever-expanding knowledge of epigenetic gene silencing is bringing us closer all the time.

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