I became a professor at HU Berlin in 2015 after 8 years as a junior group leader at IMBA, Vienna. I have enjoyed the new challenges of teaching, getting funding, setting up the new lab and establishing my new group - all those things that professors do. At the same time I reserve a proportion of my time and energy for something I have long dreamed of: being a post doc again. I have several projects of my own, both theoretical and on the bench.
Epigenetics meets mathematics
There is one paper that has most influenced my scientific thinking: Dodd et al., Cell, 2007. This was the first mechanistic theoretical model of nucleosome based epigenetic memory. For me, the important insight of this work was that epigenetic memory can be stable although individual nucleosomes constantly change their modification state. It was not until 7 years later that I had time to learn enough programming to implement such models myself, and two years after that, I met two of the authors of that paper, Kim Sneppen and Ian Dodd in Australia in 2016. I started a collaboration with Kim, that resulted in a model for PcG/TrxG regulation that combined 73 publications on PcG/TrxG biochemistry. This gave new insights into the bistable nature of the system and questioned current dogma about the role of bivalent chromatin (Sneppen and Ringrose, 2019). The bachelors project of Charlotte Hahn tested some of these ideas in vivo.
Dynamic stability. Mathematical models show how constantly changing systems can be stable.
A simple model combines a promoter and a bistable PRE/TRE with regulated coupling between them.
In silico sabbatical
In 2014-15, after Vienna and before moving to Berlin, I spent four months in the group of Martin Howard, learning to work with theorists. This led to my first and only publication so far in Cell, a documentary piece about sabbaticals. During my stay in Martin’s group I established a new model for PcG and TrxG regulation to address how Polycomb and Trithorax group proteins can maintain stable epigenetic memory for some genes, but highly dynamic regulation for others. On arriving in Berlin I continued to develop the model and experimental validation was performed by Jeannette Reinig, as part of her master’s thesis work. This work provides a simple unifying framework for a rich repertoire of PRE/TRE functions, and thus has important implications for understanding genome- wide Polycomb/Trithorax regulation. Published in Nature Communications, Sept 2020.
Epigenetics meets genetics
I have long been fascinated by the idea that DNA sequence is essential for modulating the properties of different PRE/TREs. In August 2019, after 10 years of desk work, I went back to the bench to test some of these ideas in vitro. I had built up my lab in Berlin but had never used any of the beautiful new equipment myself. On lab days, I start my day with “bench first”. Even before coffee. I get my experiment running and everything else has to fit into the incubation times. I take my timer to meetings, which helps efficiency.
I miniaturised the original 2D gel assay so that 20 samples can be processed in 3 days.
I have resurrected some experimental methods from the 1970’s and 80s, using 2D DNA gels to look at DNA structural properties. With modern equipment, I miniaturised the protocol, making it 20 - fold faster and reducing the requirement for reagents and DNA quantity by about 10 – fold. Using this rapid assay I discovered some very interesting structural properties of PRE/TREs, which may be relevant to their in vivo function. Vanessa Treffner is doing her masters thesis on this project, and Alexandra Possling has recently joined the project.