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. Jean-Philippe Babeu is the first author on ‘P1 promoter-driven HNF4α isoforms are specifically repressed by β-catenin signaling in colorectal cancer cells', published in Journal of Cell Science. Jean-Philippe is a research assistant in the lab of Francois Boudreau at Université de Sherbrooke, Sherbrooke, Canada, investigating gene regulation in the context of the gastrointestinal tract.
Jean-Philippe Babeu
How would you explain the main findings of your paper in lay terms?
Transcription factors are proteins responsible for the control of gene expression in cells. Therefore, they can control the behaviour of normal and cancerous cells through regulation of their proliferation, survival, differentiation and metabolism. Many transcription factors are expressed in different forms, known as isoforms. However, it is not well understood why the presence of different isoforms could be important or to what extent they perform specific functions in cells. In our paper, we studied a specific protein, the intestinal epithelial transcription factor HNF4α, and its two distinct isoform classes, named P1 and P2. We found that these two classes of protein control different sets of genes, allowing HNF4α to adapt its function in cells. We also discovered that, in colorectal cancer cells, an oncogenic pathway specifically blocks the expression of P1 isoforms by switching the role of HNF4α to one of tumorigenesis through the functions of the P2 isoforms.
Were there any specific challenges associated with this project? If so, how did you overcome them?
Studying isoforms is challenging because it requires tools that permit discrimination of different molecules that are very similar. In fact, the similarity between the HNF4α P1 and P2 isoform classes is greater than 90%. Therefore, being able to downregulate one isoform class specifically by means of shRNA without targeting the other was quite a challenge. We did succeed after trying many designs of shRNA that target P2 isoforms. Ultimately, generating these tools seems to me like more down to the grace of God than scientific skill!
“Studying isoforms is challenging because it requires tools that permit discrimination of different molecules that are very similar.”
When doing the research, did you have a particular result or ‘eureka’ moment that has stuck with you?
We observed that the difference in P1 and P2 isoform expression was at the mRNA level in colorectal cancer cells. However, we wondered for a while what caused the different regulation of P1 and P2 isoform mRNA in these cells. It was during a poster session in a scientific meeting that someone led me to realize that the expression gradient of HNF4α isoforms along the colonic crypt axis was pretty similar to that of the Wnt pathway. When we were back in the lab, we tried to downregulate β-catenin expression in colorectal cancer cells to see whether P1 isoform expression would be induced. When we saw for the first time that P1 isoform mRNA was specifically upregulated following β-catenin inhibition, we clearly experienced a ‘eureka’ moment!
Why did you choose Journal of Cell Science for your paper?
Principally for its scope, notoriety and the quality of studies that have been published in this journal. With the ongoing problem of predatory journals, we sought to publish in a journal that has had a solid reputation over the years and an honest peer-review evaluation. Journal of Cell Science corresponds, in our eyes, to these criteria and therefore seemed to be the best journal for the publication of our results.
The isoforms P1 and P2 of HNF4α are differently expressed along human colon crypts. While HNF4α is expressed in all epithelial colon crypt cell nuclei (purple staining), its specific P1 and P2 isoform classes are differently localized (white arrows).
“ […] my greatest dream would be to someday create and lead a research institute based on teamwork and fearlessly innovative projects.”
What's next for you?
I am working as a research assistant in an academic lab. While I cannot clearly state where I will be in the next ten years, I am looking forward to participating in many research projects on cancer or gene regulation. I am looking for new opportunities to manage projects, mentor students and maybe find financial support to start some of my own projects. I am also considering how to apply my scientific knowledge to help sick kids and their families through the creation of a non-profit organization. Finally, my greatest dream would be to someday create and lead a research institute based on teamwork and fearlessly innovative projects. While it is a utopic idea, I am a man of faith and I believe that what is not possible for man to achieve is possible for the Lord!
Jean-Philippe Babeu's contact details: Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke, QC, Canada.
E-mail: [email protected]
