Hi Yu Cheng, thanks for talking to me today. You are currently doing your PhD in neuroscience supervised by Wei-Hsiang Huang. What was academic journey before joining this group at McGill?
I come from a computer science background. My undergraduate degree at UBC was in Cognitive Systems, which is a multidisciplinary degree where you take both computer science and psychology courses. I have always been fascinated by the idea of neural networks – having connected nodes to form a big computational network.
Ah okay. Did you have any research experience from your undergrad?
Yes, I spent time in different labs, mainly in computer science and also in psychology. After undergrad, I joined a lab in Japan where I had the opportunity to work on an advanced AI model for a couple of months.
And you came to McGill for your PhD?
Well, I started my Master’s first, and then fast tracked to a PhD degree in the same research group. Coming from computer science, I had no prior biology or wet lab experience – so I had to learn everything from scratch and I thought, well, there is no better place to do that in Canada than McGill.
Why neuroscience coming from computer science?
Having studied artificial neural networks, what really excited me next was studying the natural neural network we have in our body, the nervous system, where neurons talk to each other and produce our behaviour and our thoughts. And even on a smaller level, gene networks or protein networks yielding cellular functions.
Very interesting. Last year you were funded as a D2R Scholar. How did you learn about D2R?
I was first recommended by my PI to apply for the award. He pointed out D2R because my project is really well aligned with D2R’s goals - I am rescuing animal models with neurogenetic disorders using RNA-based therapies including antisense oligonucleotides (ASOs). As I am the only person in my lab really working on RNA therapeutics, I thought it would be great to learn more about RNA from the D2R community.
That leads right into my next question about your research project. You mentioned using ASOs, but can you briefly discuss what neurogenetic diseases you’re focused on?
Yes, I study a disorder called Smith-Magenis syndrome (SMS). It is a neurodevelopmental disorder caused by low expression of the protein encoded by the RAI1 gene. It is a rare disorder that is found in 1 out of 10-15,000 children. Children with SMS are often accompanied by symptoms including obesity, autism spectrum disorders, and intellectual disabilities.
What is the function of the protein encoded by the RAI1 gene?
It is a protein that plays a critical role in neurodevelopment as it is a transcriptional regulator. So too little RAI1 expression can lead to the misregulation of many downstream genes. In SMS, the decreased expression is caused by either deletion of the part of chromosome 17 where the RAI1 gene is located or by point mutation in RAI1. In both cases, it leaves the individual with only one functional allele of RAI1.
Why do you think using an ASO will be a viable therapeutic strategy?
ASOs are usually used to decrease levels of a target RNA. Because people with SMS already have too little RAI1 protein, we want to increase overall RAI1 protein abundance by retaining it in the system for longer, so we are targeting a post-translational regulator of RAI1 called TRIM27. We recently published a discovery of this RAI1-TRIM27 axis where we showed that TRIM27 is a destabilizer of RAI1. TRIM27 ubiquitinates RAI1 leading to RAI1 degradation and we validated that decreasing TRIM27 is a feasible strategy to alleviate SMS phenotypes in cell culture.
So what’s next for the project?
After identifying TRIM27, we chose the ASO strategy as it has been shown to be a promising therapeutic option in other contexts, so we believe it will be a safe and effective treatment option. We are currently designing an ASO that targets and decreases TRIM27 and will then begin testing it in vitro and in animal models. As it’s a neurodevelopmental disease, we are planning on injecting during the neonatal period and then monitoring outcomes.
It seems like your project has somewhat organically moved towards the RNA therapeutics space. How has being part of the D2R community helped you so far?
I attended the D2R Symposium earlier this year and I talked to so many people across different fields – biostatistics, biochemistry, bioinformatics. That’s a huge value of D2R, bringing together researchers for collaboration. At the Symposium, I talked about my project with a lot of people and received feedback that I will take into consideration in my future experiments. I have received a lot of great insights from the entire RNA therapeutics community that I am excited to not only apply in my projects but also share with my lab.
I am glad that you were able to be supported by the D2R Scholar awards as the only person in your group working on RNA therapeutics. Is there anything else that you want this D2R community to know about you?
I encourage people to check out my recent publication that I mentioned earlier – we used a CRISPR screen to identify TRIM27 as a destabilizer of RAI1. Please reach out to me if you have any questions!
This conversation with D2R Training Program Officer, Anthony Van Kessel, has been edited for length and clarity.
