When we first learn about genes, we tend to be taught only a simplified picture of what takes place in nature. Like the blueprints of a house, genes contain instructions for producing the RNA and proteins that govern every aspect of life, with variations in this genetic blueprint resulting in a myriad of differences, or phenotypes. In reality, however, the path from gene to phenotype is not as straightforward as it seems.
Phenotypes are not only affected by the genetic code and gene mutations, but also by the factors that determine when and where those genes are expressed. For instance, the phenotypic consequence of switching off or silencing an otherwise functional gene is almost equivalent to that of a mutation rendering a gene non-functional.
This modulation of gene expression that is independent of changes in the genetic code, or epigenetics, is a burgeoning field that Mei Sheng Lau has spent years exploring. As a Postdoctoral Research Fellow in Wee Wei Tee’s (WWT) lab at A*STAR’s Institute of Molecular and Cell Biology (IMCB), Lau’s work focuses on epigenetic mechanisms involving chromatin, a complex of genomic DNA, RNA and proteins found within the nucleus of cells. Chromatin can be modified by a variety of biochemical reactions and differentially positioned in three-dimensional space, subsequently affecting how genes are expressed.
In this interview with A*STAR Research, Lau reveals the interwoven functions of chromatin components and gene expression outcomes and explains how the regulation of gene expression plays a critical role in development and disease.
1. What sparked your interest in biochemistry and epigenetics?
I am fascinated by the fact that the form and function of biological molecules are so elegantly connected. It is not always easy to understand how a biological molecule works. But when we eventually do, we tend to realise in hindsight how obvious it should have been based on how the molecule looks.
Chromatin is a fine example of this concept. It simultaneously enables very long DNA strands to be packaged in the confined spaces of a cell while determining which genes should be active or silenced according to different cell states.
I first learned about chromatin biology during my undergraduate studies at the University of Cambridge in the UK. I was immediately captivated by it, which spurred my desire to venture into epigenetics—a field of study where chromatin plays a prominent role.
2. Why is it important to study gene regulation at the chromatin level?
Chromatin directly influences gene regulation in many ways. For example, whether the chromatin packaging is ‘loose’ or ‘tight’ has direct implications on cell function. An illustration of this is in stem cells which generally contain more loosely packaged chromatin. This structure allows a stem cell to have a higher degree of plasticity and to retain its ability to develop into other specialised cell types. As a stem cell differentiates and specialises, the chromatin within it becomes increasingly ‘tight’ and permanently represses the genes associated with other now-irrelevant cell lineages. In this way, chromatin locks in the cell’s identity at each developmental stage. Another example is chromatin folding in three-dimensional space, which physically brings together related genes so that they can be regulated in close coordination.
Chromatin’s critical role is made clear by the large number of disease-associated mutations in genes that code for chromatin components. Some of these genes, like EZH2 and BRD4, are now important drug targets in cancer therapeutics. As such, they advance our understanding of how chromatin functions have important implications for disease therapeutics.
3. How has your research direction evolved since completing your PhD degree?
In my PhD research project, I mainly investigated the role of chromatin components called Polycomb group proteins in transcriptional regulation—how they normally work and the corresponding consequences on development and disease when their function is disrupted.
While I still study chromatin function, the scope of my research has broadened. One of my current projects involves investigating the influence of DNA in the chromatin complex, which is the lesser-studied component in chromatin, and epigenetic silencing. I am also exploring how we can use information in chromatin for predictive and engineering purposes. For example, chromatin status can be used to predict whether a particular cell source would be suitable for cell-based therapy. With that knowledge, we can also alter other cell sources to improve their suitability for therapeutic applications.
4. How have A*STAR and the WWT lab supported your growth as a young scientist?
A*STAR’s National Science Scholarship made it possible for me to pursue a world-class education without the financial burden. As a scholar, I had the opportunity to be involved in other aspects of science, like recruiting young talent through A*STAR’s scholarship programmes, participating in public outreach initiatives and being a part of policymaking and event planning. These experiences gave me a more holistic view of the scientific ecosystem.
As a Research Fellow now, I appreciate the support IMCB offers to relatively new labs like ours. The WWT lab was just established when I joined, so I experienced the challenges faced by a small lab trying to make a name for itself. I am thankful to my supervisor Wee Wei Tee, who worked relentlessly to ensure that my colleagues and I had the right environment and resources we needed to carry out our research.
5. What research problems do you hope to address in the next decade?
I want to apply my knowledge in chromatin biology to study heterogeneous and complex neurodevelopmental disorders like autism spectrum disorder (ASD). Among the many risk genes identified for ASD, more than half of them surprisingly code for chromatin factors and gene expression regulators. This suggests that chromatin plays a significant role in the mechanisms underlying ASD. I welcome potential research partners with complementary domain knowledge and the relevant skills to join me in my quest to uncover more answers.
