Bioinformatics can reveal the role of genes in the human body without us even having to don a lab coat. Two such genes, ULK1 and ULK2, may look similar but recent research has shown them to play diverse and important roles in autophagy and disease, among many other things.
Bioinformatics can reveal the role of genes in the human body without us even having to don a lab coat. Two such genes, ULK1 and ULK2, may look similar but recent research has shown them to play diverse and important roles in autophagy and disease, among many other things.
Amanda Demeter, who has been working with the Korcsmaros and Macaulay Groups at EI, tells us about the power of bioinformatics and how she is making discoveries by using systems biology to look at the bigger picture.
When I started my masters in Biology, we had our first bioinformatics course. I found it quite cool and was inspired by the type of topics and projects they mentioned, so I got in touch with the group leader who was giving the course to ask about possibilities in the group. This was Tamas Korcsmaros, who went on to become my supervisor for my masters project, and later on for my PhD.
I think one is that it is definitely more flexible than lab work. I wouldn’t say this means ‘easier’, it is just that maybe you can control it better. Troubleshooting in the lab can take lots of extra time before you see any results - and also money because of consumables.
Bioinformatics is very much an evolving area, gaining more and more importance as a standalone discipline but also in the way it complements lab experiments.
At the moment I’m working on a project that combines the wet lab with computational biology. We are implementing a protocol in the single-cell lab that makes it possible to take a cell and assess its DNA and RNA, and from the DNA to understand methylation and chromatin accessibility.
This is important because we could have information about the functional state of the cell and also about its regulation.
The point of the project was to compare the function of two paralog genes, ULK1 and ULK2. These are genes in an organism, in our case human, that duplicated during evolution.
ULK1 and ULK2 look very similar at first sight. Their role is known in autophagy - a self-eating process of our cells, which happens normally but can also be induced by stress - where components that are no longer needed, or even pathogenic bacteria, are degraded.
It seems like ULK1 has a bigger role in that than ULK2, and a few experiments show differences between ULK1 and ULK2 in other cellular processes like lipid metabolism. The exciting thing is that, so far, most researchers have considered ULK1 and ULK2 so similar that they haven’t investigated any unique roles or differences between them.
Prompted by this, our aim was to compare the two genes, and also the proteins which the genes are translated into, using network biology and other bioinformatics approaches.
This was a purely computational project and we used various databases to investigate differences in structure, expression, function and how the proteins interact with other molecules at the systems-level: looking at the bigger picture.
We found that there are indeed many important functions that are specific to ULK1 or ULK2, meaning that they can have very different roles.
Structure-wise, even though they have the same kinase domain, they have specific protein motifs - these are short amino acid sequences along the protein that serve as a target surface for other proteins to bind to. As there are motifs on both proteins that are not present on the other one, we can expect that the subsequent interactions result in specific functions.
Another finding was how different their promoter region is. The promoter is a region before genes, which transcription factors can bind to and thus affect the transcription of the gene. We found that the promoter of ULK1 and ULK2 genes can be regulated by different transcription factors, which can also result in ULK1 and ULK2 having specific functions.
One of the key findings was that the ULK1 and ULK2 proteins are connected to different proteins even within the group of autophagy-related ones, and those proteins are related to specific autophagy types. Namely, specific binding partners of ULK1 are involved in digestion of superfluous mitochondria and the specific binding partners of ULK2 are more involved in xenophagy - the degradation of pathogens by human cells (and not just the immune ones!).
By looking at the interaction partners - direct interactions with proteins, or regulating transcription factors - we found that interacting partners of ULK1 are predominantly associated with intracellular transport, stress response, apoptosis and chromatin organisation, whereas interacting partners of ULK2 are associated with nitrogen compound metabolism, homeostasis and response to cytokines.
ULK1 and ULK2 were thought to be redundant for quite some time, and even though there were some examples of the opposite in specific functions, our work was the first to point out a whole set of functional differences.
As we discuss in the article, this could lead to a better understanding of diseases and a better description of the role of autophagy in diseases. We found the expression of ULK2, but not ULK1, is decreased in ulcerative colitis - this is an inflammatory bowel disease. This is one of the things that suggests there may be a more complex regulation between the paralogs and it is worth investigating them as separate genes/proteins.
I probably most enjoy the flexibility. If you know the right techniques, you can analyse a huge amount of data quite quickly and, for my projects, I needed only my computer.
Personally, I also find it very cool! On the other hand, it can be challenging to find the right resources to use when you need to include existing data in your analysis.
Not really. Previously, I was more interested in anatomy and microbiology. It also depends on which research groups are approachable or experienced, and I think I was very lucky in the end. Fortunately for me, I was able to get involved in a project that involved microbiology too, as I was working with Salmonella.
I can’t really speak for other institutes but, based on what I see at EI or in the groups of collaborators I have worked with, I can definitely see women being interested in and working in bioinformatics. I think it’s important, regardless of gender, that people from every field share their career experiences so students of all backgrounds have the most information possible to help them choose a career.
I really liked it when they found phosphine in Venus’s atmosphere. [Perhaps a hint at extraterrestrial life living, most unexpectedly, in her clouds of sulphuric acid. Although recent conflicting results have put that finding in doubt, which is a great example of the scientific process at work.]
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