Thesis defense Franka Rang ‘Decoding Developmental Epigenetics: Innovation and implementation of single-cell techniques to study epigenetic regulation in embryonic development’

Every cell in our body contains the same DNA, the genetic information that acts as a blueprint to make the proteins needed for cell functions. Even though all cells have the same DNA, they look different and perform different roles by using only specific parts of their DNA through a process called gene expressionThe activity of a gene or genes. The combination of active genes in a cell determines, amongst other things, the function, shape and size of the cell.. Gene expression is regulated by the epigenome, an additional layer of information that controls which parts of the DNA are (in)active, without changing the DNA itself. This is mainly accomplished through interactions between DNA and regulatory proteins, which are referred to as protein-DNA interactions. Such epigenetic mechanisms are especially important during embryonic development. Through epigenetic regulation, the embryo is able to develop from a single cell into a whole complex organism, consisting of many different cell types. Understanding how the epigenome controls gene expression is key to understanding embryonic development.

Measuring epigenetic regulation in individual cells

During her PhD, Rang and her colleagues developed an innovative technique named scDam&T-seq. This technique simultaneously measures protein-DNA interactions and gene expression in individual cells. Measuring this on a single-cell level is especially important because gene regulation is different for each individual cell. Rang says: “By doing this in single cells, we can directly relate the protein-DNA interactions with gene expression.” Rang and colleagues extended this technique to also detect modifications of specific proteins, named histones. These so-called histoneProteins in the nucleus around which the DNA is wound. This way, all the DNA fits inside the nucleus. Through modifications of the histones, the DNA is wound tighter or looser, which changes the accessibility of the genes in that area. modifications, play a critical role in epigenetic regulation. This technological extension is called EpiDamID.

Epigenetic state defines genome architecture

Both techniques open up new avenues of research. For example, Rang herself was able to use these techniques to gain a better understanding of how genomeThe complete set of DNA or genetic material in a cell. organization plays a role in early development. Rang explains: “The spatial organization of the genome of early mouse embryos is highly variable and this variability is a unique aspect of the genome during early development.” By using scDam&T-seq and EpiDamID, Rang established that those high levels of variability in spatial organization between embryos is due to embryo-specific patterns of histone modifications. These findings contribute to our understanding of the process of early development, which may yield benefits for tackling developmental disorders. Furthermore, the relationship between epigenetics and spatial genome organization likely extends to other biological systems and these findings may therefore help in tackling diseases with an epigenetic component, such as cancer.

Colleagues make the PhD

Rang has had a great time during her PhD at Hubrecht Institute. She was very happy with her colleagues, which she describes as ‘awesome’. Especially the lab retreats with the Kind Group were a highlight during her PhD years. It’s therefore not surprising that the COVID lockdown, during which she was not able to see her colleagues, was the most challenging time of her PhD. The publishing process can be painstakingly slow, so Rang can truly be proud of her first-author papers and making it through this process with her co-authors Kim, Sandra and Isabel.

Take control of your own research

Rang has some valuable advice for other PhD students: “You have more influence on your research than you think: Don’t just do what you think others want, but include your own ideas, goals and timelines and communicate those clearly.” She also wants to save fellow students from a formatting nightmare by reminding them to save all files that are being created during the publishing process of papers and chapters.