ABSTRACT
First Person is a series of interviews with the first authors of a selection of papers published in Journal of Cell Science, helping early-career researchers promote themselves alongside their papers. Izzy Owen is first author on ‘ The oncogenic transcription factor FUS-CHOP can undergo nuclear liquid–liquid phase separation’, published in JCS. Izzy is a PhD student in the lab of Frank Shewmaker at Uniformed Services University of the Health Sciences, Bethesda, USA, where her research interests involve understanding protein phase separation at the molecular and functional levels in disease.
Izzy Owen
How would you explain the main findings of your paper in lay terms?
Cancer is often driven by specific oncogenic proteins. This work focuses on an oncogenic fusion protein known as FUS-CHOP, which causes myxoid liposarcoma. It was previously understood that expression of FUS-CHOP in cells results in tumor formation, but the mechanism was unknown. The previous work in our lab focused on the ability of FUS to undergo liquid–liquid phase separation (LLPS), which is a phenomenon in which certain proteins and nucleic acids condense into distinct liquid structures where different cellular functions occur. Cellular phase separation is often compared to an oil droplet in water, with two liquid phases existing together, but separated. Our research suggests that the FUS portion of the FUS-CHOP fusion drives LLPS in the nucleus of cells, whereas CHOP alone does not have this property. We show that phase-separated FUS-CHOP recruits transcriptional proteins in the nucleus, which could explain the unique gene expression pattern that occurs during oncogenesis and tumor formation. These findings have potential application in creating targeted therapies for patients who suffer from myxoid liposarcoma.
Were there any specific challenges associated with this project? If so, how did you overcome them?
This project was a new avenue for the lab. Our previous work focused on the role of FUS in neurodegenerative diseases, so understanding the protein's role in cancer was something we had never studied. It was a fantastic opportunity to expand my research interests and characterize similarities of pathogenic FUS in both neurodegeneration and cancer. It was fundamentally challenging because it was our first project focused on molecular cancer biology, requiring development of new methodologies and knowledge. The most technically challenging aspect was visualizing condensate fusion over both time and space. To do this, we had to develop novel microscopic methods to capture the quick fusion events while also rendering the cell in three dimensions. It took several trials with the confocal microscope to determine the best settings to effectively collect these data.
When doing the research, did you have a particular result or ‘eureka’ moment that has stuck with you?
The ‘eureka’ moment occurred in the very early planning stages of this project. FUS-CHOP had been researched in depth in 1990s and early 2000s, but since then very little work had focused on understanding the protein's properties. The field of phase separation has rapidly advanced and there had been suggestion of oncogenic phase separation, but no concrete examples. Combining my knowledge of FUS and the previous literature surrounding FUS-CHOP, we were able to define the FUS-driven phase separation phenomena in cancer and fill in a lot of the blanks from 20 years ago.
Why did you choose Journal of Cell Science for your paper?
Journal of Cell Science is known for publishing cutting edge research in both cell and molecular biology. JCS also has a quick and effective review process, which we felt was important for the timely publication of our work. Our work's focus on the molecular details of protein phase separation, while also thinking about mechanisms underlying cellular transformation, seemed like a perfect fit for JCS.
Have you had any significant mentors who have helped you beyond supervision in the lab? How was their guidance special?
My direct mentor, Frank Shewmaker, has been instrumental in both science and career guidance over the past four years. Studying oncogenic fusion proteins was not originally part of his research program, but he supported my ideas and encouraged me to develop independent goals. We also discussed practical issues for navigating life, graduate school, family and career options. I'm grateful for this type of intellectual environment because it helped me reach higher standards and achieve greater goals.
FUS-CHOP–eGFP condensates recruit phase separating super-enhancer protein BRD4. FUS-CHOP-eGFP phase separates upon ectopic expression in NIH 3T3 cells. Using anti-BRD4 antibody, we observed recruitment of BRD4 to large FUS-CHOP condensates.
FUS-CHOP–eGFP condensates recruit phase separating super-enhancer protein BRD4. FUS-CHOP-eGFP phase separates upon ectopic expression in NIH 3T3 cells. Using anti-BRD4 antibody, we observed recruitment of BRD4 to large FUS-CHOP condensates.
What motivated you to pursue a career in science, and what have been the most interesting moments on the path that led you to where you are now?
I was always motivated by the unknown. I learned early that the more you know, the more you realize how much is unexplained. Human biology is full of unanswered questions, and, unfortunately, some of these unknown variables cause disease. I am pursuing a career in science because I am motivated, intelligent and driven to explore that which is undiscovered in biology. I hope to see new knowledge translated into treatments for human diseases.
“I learned early that the more you know, the more you realize how much is unexplained.”
Who are your role models in science? Why?
Jennifer Doudna is one of my scientific role models because she is a strong, brilliant and tenacious scientist. Her work involving CRISPR has been monumental in all fields of biology. She came to our university and spoke about her journey and how she navigated through all of the challenges of fundamental biological research. She was humble and a great example and motivator for young scientists like myself.
What's next for you?
In the fall, I will be starting a post-doctoral position in the Neuroscience Research Institute at Allegheny General Hospital in Pittsburgh, PA. My future goal is to pursue a research position in industry because I want to be more involved in the application and development of scientific advances. I would love to be part of a company whose research directly impacts patients' lives and well-being.
Tell us something interesting about yourself that wouldn't be on your CV
I was a captain of the cheerleading squad in middle school, high school and college. It was a passion of mine and I haven't found many scientists who share the same sentiments!
Izzy Owen's contact details: Uniformed Services University of the Health Sciences, Bethesda, MD 20814, USA.
E-mail: [email protected]
