Jernej Ule from University College London, UK, has spent his entire career studying how and where RNA-binding proteins bind to RNA, and what their function is in doing so. Together with John Rinn from Harvard University, USA, he recently Guest Edited an issue of Genome Biology focused on this very concept: RNA-binding proteins and their recognition elements in the transcriptome, or – as Genome Biology have dubbed it – ‘the RBPome’.
The issue provides a picture of the emerging themes in this blossoming field. An overview of what is included can be found here, while Rinn and Ule’s general thoughts on the RBPome are discussed in their Editorial. Biome has highlighted some of the most interesting pieces of research included in the RBPome issue, as has the BioMed Central blog. Here Ule shares the story of how he became interested in the RBPome and the scientific journey that it has taken him on.
Why did you become interested in the RBPome at the very start of your career? I understand that you did a PhD with Robert Darnell, is that where it began?
Even before working with Bob, I started becoming interested in RNA because I was interested in the way the brain can adapt to stimuli or can be affected by disease. At the time I was working in a lab that was studying dopaminergic signaling and Parkinson’s disease, and so forth, and there was more and more evidence that there was an aspect of biology that was completely overlooked at the time. New technologies were becoming available from the genomic angle, so that was the reason why we became interested in Bob’s lab originally.
Then, when I was in Bob’s lab, my goal was to understand what one particular RNA-binding protein does to cause disease. It was clear that this protein was associated with disease, but nobody had an idea why this protein is specific to one particular disease. My approach was to figure out what it binds to, so that was the starting point of a long line of research looking at a variety of methods that could delineate the network that the protein controls.
In fact, it turned out that this wasn’t a fishing trip. Even though we identified dozens of different RNAs, they all converged on one single function; they all encoded proteins involving the synapse. By following these specific RNAs and their function and regulation, Bob could then develop better models for the disease.
What do you think the take home message is from the Genome Biology RBPome issue?
Definitely that a lot of progress has been made in the last years in both genomic tools and data analysis, so that any RNA biology lab – even without expertise in genomics – can now use available public computational software as well as methods that are well established. So RNA genomics and RBPomics has become a standard tool that can be established in most labs. It’s no longer a technique that is exclusive to just people with expertise. I would say this is one of the take-home messages.
On the other hand, there’s also many remaining to be explored. The tools are available but there are a lot of questions to still be answered with the available data. So there’s a big opportunity right now to move the field of RNA biology toward a more systems-wide approach.
When research into the RBPome began most people were molecular biology driven and very few were looking at it from a genomics point of view, as you were. This is no longer the case; how has this affected your career?
For me personally, even just a few years ago I would feel I had an advantage by knowing how to do CLIP well. This is not an advantage now at all because it’s a method that’s become very easy and lots and lots of labs have established it. So this pushes me into applications of the method that are more linked to disease, and very specific biological questions. I’m no longer focused on method development. It releases me from that pressure. So many people have contributed to this field now that I can go back to these primary biological questions that I was always interested in. We have actually been spending a lot of time just to be able to get to the point where I started!
Are there any particular exciting developments or future prospects for the RBPome field that you think people should be looking out for?
On the one hand you have this epitranscriptomics field, as it’s called nowadays, which looks at how RNA-binding proteins generate modifications on RNA in a similar way as DNA methylation. Both RNA and DNA can be a pretty rich template for further modifications. The most studied RNA modifications so far have been those on non-coding RNAs, but it’s becoming clear that mRNAs are also potential targets.
On the other hand, there is a lot of research right now into the disease relevance of RNA, because of the data and the technology that has recently become available. It’s just a big opportunity. So far there has been a focus on transcription and I believe that the link to disease will become the really big topic in the next years. Also therapeutic and biotechnological applications of RNA biology, from CRISPRs and genome editing to RNA vaccines and different types of antisense RNAs. In a way, original genetic engineering tools were very clumsy compared with the tools that we can now use with the recent findings from RNA biology.
Would you say that CRISPR looks set to follow a similar trajectory to high-throughput sequencing, in the sense that it will have applications across a range of fields?
Very much so. It’s a perfect combination because CRISPR now allows you to give a functional angle to genomics. With high-throughput sequencing, we were often characterizing interactions between molecules. For RNA biology, it was very powerful for methods like CLIP, where you could study the physical interactions between RNA and proteins. But we also need to understand what these proteins are doing to the RNAs. So we can now have tools to really systematically characterize individual interactions and perturb their sequence or structure. We can somehow put the two pieces together and CRISPR should be just perfect for this.
Questions from Naomi Attar (@naomiattar), Senior Editor for Genome Biology.