Rob Martienssen, Cold Spring Harbor Laboratory
Kat:: Now itís time to take a look at some of the most interesting molecular players in the world of epigenetics: small RNAs. Many of the talks at the symposium focused on RNA - a kind of molecular Ďcousiní of DNA, which is made when DNA is read, or transcribed. Researchers are now finding more and more roles for these little fragments in controlling how genes are turned on and off - and their effects may potentially even travel across generations. To get the low-down I caught up with Rob Martienssen, from Cold Spring Harbor Laboratory in New York.
Rob - So, small RNAs were discovered in probably the late Ď90s but they turn out to be everywhere pretty much. So, we work on looking at these short RNA sequences, specifically the ones that regulate transposable elements, repetitive, junk DNA, things that were thought not to be important for a long time. But actually, we think are hugely important parts of genomes that control epigenetic inheritance.
Kat - Thatís a big word. What do you mean by epigenetic inheritance? How would you describe that?
Rob - Usually, we think of inheritance as being the inheritance of changes to our DNA sequence, to our genome sequence. But epigenetic inheritance are modifications of that sequence that can be reversed or changed and are not fixed in the same way that DNA sequence changes are. But they can be just as important. Importantly, you have to think about how they could be guided to specific DNA sequences that they would modify in some way that would allow that to be inherited. And so, we think that small RNAs are very important in how that inheritance happens.
Kat - So, this is basically how our cells or how any organism's cells manage to kind of be a bit more responsive or responds to the changes in the environment around them and have different types of cells.
Rob - Thatís right and importantly, how they control their transposable elements which can occur over generations, actually first shown year ago by Barbara McClintock, who described something called cycling where transposons would go on and off over, not just a few cell divisions but over actual generations like multiple generations.
Kat - So, tell me a little bit more about these small RNAs. What do they look like, how are they made, and what do we think they're doing?
Rob - So, the small RNAs are short nucleotide sequences, about 20 to 30 nucleotides long.
Kat - Thatís kind of letters of RNA.
Rob - Right, letters of RNA that correspond very closely to the letters of DNA and thatís how they can recognise particular genes or transposons in the genome. They're actually almost the perfect length to do that within a genome of the size of a human genome or of the maize genome. What they seem to do is they bind to specific proteins called argonaute proteins. There are many, many different argonaute proteins that bind the small RNA and allow them to match a corresponding sequence in a target RNA. The target RNA in many cases gets cleaved by the argonaute protein which is actually an enzyme that can break RNA.
Kat - So, they basically chops it all up and gets rid of it.
Rob - More or less. It actually does more than that because it seems like that process of chopping it up and getting rid of it also guides, targets other enzymes that modify either the DNA by DNA methylation or the proteins that DNA surrounds Ė the histones, chromatin, we call the ensemble of all of that. These also get modified in response to that processing of RNA. Itís one of the things we work on. We still havenít exactly figured out how that happens, but a lot of work has been done especially in plants and in fission yeast.
Kat - I find this whole process really fascinating that you have these tiny little fragments of RNA, they seek out things that they match and then almost like - the magic happens! This is how genes can get switched off, can get silenced. What do we know about how important this is in regular life for cells or for plants? We know that it is maybe important for shutting off these jumping genes, these transposons, but what do these small RNAs do in kind of regular biochemistry?
Rob - They do a lot. They also target genes. When they target a gene of course, they can turn the gene on and off. And so, itís a very powerful control mechanism both in normal development in humans, in plants, also in animals. And importantly, in cancer and a lot of diseases, some of these small RNAs are very, very important and prevalent in regulating genes in that way. They can also influence everything in plant development. For example, one of my favourites is plants have a juvenile and an adult phase, just as Ė think of a teenager, adultÖ
Kat - A teenage plant!
Rob - This difference is actually completely controlled by small RNAs. There's one thatís specific to juvenile phase, one specific to the adult and they regulate each other and itís a fantastic story.
Kat - Given how widespread these tiny little RNAs seem to be and how people are finding them in more and more organisms and doing more and more things, is it safe to say that they're pretty much involved in everything when it comes to controlling genes? Is there anything they canít do?
Rob - That's actually not far off the case. Literally, half the transposons in the model plant we like to use, Arabidopsis, are targeted in this way - something in the order of 500 genes. In humans, estimates vary but certainly, thousands and thousands of genes are regulated by small RNAs. It could be that every gene is regulated by small RNA.
Kat - We just havenít found it yet. They're so small!
Rob - Exactly.
Kat - Where next do you think for this field? Lots and lots of people are identifying these small RNAs, trying to figure out how they work, how they regulate genes, how they control them. Where do you think things are going?
Rob - There's a lot of interest in connecting the epigenetics Ė thatís the heritable things that happen to DNA Ė to the small RNAs. Thatís field has been really exploding in the last few years and I think in the next few years, it will come to a conclusion which will be very exciting. I think inheritance of the small RNAs themselves, or at least of their effects. In plants, itís probably more well-established that this could happen. In humans, are beginning to look into that.
Kat - So, thatís from generation to generation rather than just cells divide.
Rob - Thatís right. So I mean, there are some people who are really beginning to say that maybe germ cells, sperms and eggs actually contain a lot. They contain a huge amount of RNA. It could be that this is actually transmitted in some way. There's also new types of small RNAs, so they're continually being discovered. One of my personal interest is recently, genome editing has been shown to be controlled by a type of non-coding RNA thatís found in bacteria. Itís work brilliantly well in ourselves as well. I'm wondering if the mechanism might be somehow related. Thatís going to be a fun area because we know recently that small RNAs are involved in DNA repair. I think thatís going to be an important area as well.
Kat - Given how important these small RNAs seem to be and how easy it is maybe to make them and to manipulate them, are there any therapeutic implications? Maybe we could develop medicines or ways of gene therapy using these things.
Rob - There is a lot of interest in that. Several start-up companies have done very well on that specific idea. Using the RNA exactly as it is, it probably needs some modifications to make it useful as a drug, but itís definitely a big area. In plants, some seed companies are thinking of spraying plants with small RNA. Itís something that I was very sceptical about but apparently it works. I think thatís going to be a big area, absolutely.