EDLYN WU
Research
Fish and worm tales.
Discovering mechanisms underlying genome activation of the developing zebrafish embryo and the mechanism of action by microRNAs in mRNA silencing in the C.elegans embryo
Sleeping embryonic genomes are awoken by OBOX proteins
Postdoctoral research
At fertilization, the animal genome is inactive, and the earliest stages of development are driven by pre-existing proteins and RNA transcripts that have been stored in the egg. As the fertilized egg divides into two cells, developmental control is gradually handed over to the embryo. The pre-existing RNA (known as maternally loaded RNA) is degraded, and the embryonic genome (called the zygotic genome) is activated. Commissioned by Nature to write a News & Views article, we highlight the recent publication from Ji et al. which describe the identification of a family of transcription factors involved in kick-starting the zygotic transcription program in mice, and provide evidence that these factors have a role in targeting the transcriptional machinery to the correct genes.
The interplay between transcription factors
and RNA-binding proteins in transcription bodies
Postdoctoral research
In animals, early embryo development relies entirely on maternally supplied mRNAs and proteins. These maternal products are important not only for survival, but also to gear up for zygotic genome activation (ZGA). In the last decade, several key transcription factors have been identified as master regulators of genome activation. However, the molecular mechanism that kickstarts the transcription program in the developing embryo remains unclear. For my postdoc, I joined the lab of Dr. Nadine Vastenhouw to understand the molecular landscape in the early embryo, while at the same time, expanding the zebrafish biochemical toolkit. I identified an RNA-binding protein that interacts with one of the master regulators of ZGA. This RNA binding protein is also enriched in transcription bodies. I am currently characterizing this factor to understand its role in ZGA.
The role of Nanog in transcriptional organization
Postdoc • Design and cloning of Nanog constructs, figure design and data visualization
Transcriptional activity is compartmentalized in our cells. How the transcriptional machinery come together on DNA to form such compartments is not clear. The zebrafish embryo, being transparent, is a good system to visualize the dynamics of different players assembling inside transcription bodies. What is the behaviour of some of these factors and what is the order of events leading up to gene expression? This project was led by first-author, Ksenia Kuznetsova. I made the constructs to dissect the role of Nanog, which we discovered to be a key component in organizing transcription bodies. I also contributed to the data visualization and figure design.
MicroRNAs and gene silencing
PhD research
During my PhD, I integrated biochemistry, proteomics, cell-free assays, and genetics, to provide a greater understanding of the mechanism of gene silencing by microRNAs. I aimed to resolve and delineate the temporal order of events during microRNA-mediated silencing: from target recognition by miRISC, to the recruitment of the effector CCR4-NOT complex assembly on target mRNAs, in nucleating a microenvironment that drive target mRNA silencing. The model on the right illustrates the mRNP assembly and specialization on target mRNAs in embryonic miRNA-mediated silencing. My work improves on our understanding of miRISC interactions, and opens up new possibilities into how developmental contexts modulate silencing mechanisms dictated by microRNAs.
C. elegans: from genetics to biochemical toolbox
PhD research • toolbox developer
The nematode C. elegans has an extensive resume with diverse genetic approaches that has established a framework for the many regulatory pathways that govern animal development. However powerful, genetics also has limitations that were recognized early on by Sydney Brenner (pioneer of the use of C. elegans) himself: “only when genetics was coupled with methods of analyzing other properties of the mutants, by assays of enzymes or in vitro assembly, did the full power of this approach develop” (Brenner, 1974). To truly understand the mechanism of action for gene silencing by microRNAs, I first embarked on an adventure to develop an extract from C. elegans embryos. I succeeded in extending the resume of C. elegans and adding 'biochemical toolbox'. This system served as an invaluable tool throughout my thesis work.
MicroRNAs in Cancer
Figure design and manuscript revision
In addition to using the nematode C. elegans to study the fundamental mechanism of microRNA-mediated gene silencing, the lab of Dr. Thomas Duchaine is also interested in understanding the processing of miRNAs. In humans and mice, the miR-17~92 polycistron encodes six microRNAs, and has been shown to display oncogenic activity when the microRNAs are overexpressed, such as in diffuse B cell lymphoma. As co-transcriptional processing of primary miRNA transcripts is an important step in miRNA biogenesis, what is the impact of the miRNA machinery on pri-miRNA transcription and maturation? For this project, I helped with the data visualization and figure designs.