First person – Zhi Yang Tan Free

Zhi Yang Tan

How would you explain the main findings of your paper in lay terms?

In cells, misregulation of chromatin organisation disrupts essential nuclear processes and is associated with diseases like cancer. In this paper, we use G0 fission yeast – which are characterised by compact chromatin, low histone acetylation, low transcription and increased thermotolerance – as a model to understand the relationship between these factors. Surprisingly, we find that artificially increasing histone acetylation in cells attempting to enter the G0 state leads to higher DNA content and larger nuclei but has no observable effect on nuclear complex organisation or transcription. The cells still exhibit the increased thermotolerance characteristic of G0. These results show that the fission yeast G0 state, chromatin organisation, histone acetylation and transcription do not have a simple causative relationship, highlighting the complexity of the regulation of nuclear processes.

Were there any specific challenges associated with this project? If so, how did you overcome them?

The biggest challenge was determining chromatin compaction in different states of fission yeast nuclei. This was complicated by the rarity of canonical nucleosomes resembling the nucleosome crystal structure previously identified by Luger et al. (1997) in situ, making nucleosome identification impossible. We first tried another method of measuring the crowding of macromolecular complexes using Fourier analysis, but this method also showed no changes in macromolecular complex crowding. To convince ourselves that the absence of identified canonical nucleosomes and the lack of macromolecular complex crowding changes were biological, rather than a technical phenomenon, we prepared and analysed additional replicate tomograms of different fission yeast nuclei states.

When doing the research, did you have a particular result or ‘eureka’ moment that has stuck with you?

The moment I successfully used 5-ethynyluridine to label the RNA in Schizosaccharomyces pombe for the first time left a long impression on me. Although this chemical had long been used for RNA labelling, other labs had mainly used it in animal cells. Compared to the bromouridine that is often used for fission yeast RNA labelling, which usually requires additional antibody treatment steps and did not work well in our hands, 5-ethynyluridine enabled us to perform RNA labelling experiments much more easily. In the end, we were surprised by how powerful 5-ethynyluridine labelling was.

Why did you choose Journal of Cell Science for your paper?

In addition to Journal of Cell Science's focus on cell biology, which our paper aligns well with, JCS also values the importance of ‘negative’ results in research. JCS recognises that new knowledge can be gained even from results that contradict expectations – an aspect reflected in some of our results.

Have you had any significant mentors who have helped you beyond supervision in the lab? How was their guidance special?

The supervision I received from Associate Professor Lu Gan extended far beyond supervising my experiments. During my PhD, I was nurtured to take on the full responsibilities of a PI, including experimental workflows, safety procedures, lab material procurement, scientific writing and securing lab funding. Under Professor Lu's extraordinary mentorship, I became a much more independent researcher and was able to immediately apply my lab management skills when commissioning a new wet lab in my current postdoc position.

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?

My family has a medical health history of hypertrophic cardiomyopathy (HCM), which inspired me to pursue a career in science to identify and treat human genetic diseases. As early as my first year in the NUS High School of Math & Science in Singapore (when I was 13 years old), I found lab work in science practical sessions very interesting, and I was always fascinated by the results. In my fourth year, I enjoyed my first real taste of research experience at Temasek Life Sciences Laboratory (Singapore). Later, during my undergraduate final year project under Associate Professor Lu Gan, I successfully created a genetically modified budding yeast strain with all copies of a histone tagged with green fluorescent protein. This strain exhibited observable additional densities in cryoelectron tomography (cryo-ET) 3D class averages and later became essential for another paper I published (Tan et al., 2023). Seeing its potential to advance cryo-ET research on nucleosomes motivated me to continue my PhD in Professor Lu's lab. All these experiences confirmed that a career in science was a good fit for me.

Who are your role models in science? Why?

I have always been inspired by Thomas Edison, especially his quote, “Genius is 1% inspiration and 99% perspiration”. This shaped my work ethic, reinforcing that research is not just about having the right ideas but also about hard work and perseverance through failure. Another lesser known of his quotes, “I have not failed. I've just found 10,000 ways that won't work”, also resonates deeply with me. It serves as both a reminder to persevere through failure and an often forgotten message: in science, negative results are just as important – if not more so – than positive ones.

What's next for you?

I am currently a postdoc in Assistant Professor Liu Boxiang's lab at the Department of Pharmacy and Pharmaceutical Sciences, National University of Singapore, which focuses on the genetics and genomics of complex diseases. Here, I aim to advance my skills in bioinformatics and genetic modification of human cells. Together with my expertise in cryoelectron microscopy, these skills will position me well for future research opportunities, whether in academia or industry.

Tell us something interesting about yourself that wouldn't be on your CV

Though I don't have much time now, I enjoy travelling to other countries.