2 PhD positions investigating the molecular mechanisms in epigenetic inheritance at the Institute of Molecular Biology in Mainz, Germany

Posted on November 8,

The laboratory of René Ketting at the Institute of Molecular Biology (in Mainz, Germany) is looking for two motivated PhD students to work on deciphering molecular mechanisms in epigenetic inheritance within the framework of the International PhD Programme (IPP) on Gene Regulation, Epigenetics & Genome Stability.

Small RNA molecules are extremely potent regulators of gene expression. Research by many teams, including ours, has demonstrated that small RNAs can act in many, mechanistically diverse mechanisms. A common theme is that many of these pathways act to silence molecular parasites, such as transposable elements, in germ cells, and as such act as the genome’s immune system. Understanding their molecular mechanisms will help us to understand how genomes can distinguish between self and non-self.

Small RNA pathways are typically found in so-called germ granules. These are phase-separated structures, and over the past years it has become clear that phase separation is a concept with a broad impact on cellular function. This makes germ granules an attractive model system to study how phase separation may contribute to cellular function in general. Our recent work shows that  germ granules can perform very specific tasks in the inheritance of small RNA molecules, but also mRNAs, between generations. Our work is largely aimed at deciphering the molecular mechanisms and biological relevance of germ granules, with the aim to understand epigenetic inheritance, and in the longer term to understand how phase separation contributes to subcellular organization in general.

Both projects will make extensive use of Crispr-Cas9 mediated gene editing and genetics. In addition, we are using structure predictions and biochemistry to study the proteins of interest in relation to their enzymatic activities and/or interactions with other proteins and RNA. Most projects in our group are performed in a collaborative setting with different groups within IMB, on campus and abroad.

PhD Project 1: Mechanisms of paternal epigenetic inheritance
In this project we will study the molecular mechanisms that drive the assembly and enable the function of so-called PEI granules (Schreier et al. 2022). These granules enable inheritance of small RNAs via the sperm and contribute to germ cell development in the embryo. However, the precise functions of the PEI granule components are still unknown. In this work we will closely collaborate with the group of Lukas Stelzl (also IMB), who uses multi-scale simulations to identify critical processes that drive PEI granule assembly and function. In this very interdisciplinary project we aim to understand how PEI granules form, how and why they interact with membranes and how they achieve the exquisite specificity that we have observed in vivo.

PhD Project 2: piRNA biogenesis in C. elegans
We have recently identified a new nuclease that is essential for the biogenesis of a small RNA type named piRNA. This yet unpublished work is a close collaboration with Sebastian Falk at the Max Perutz in Vienna, and we are looking for candidates to follow up on the many exciting findings that we have done in the course of this project. First, we will study how this enzyme works in nematodes, using biochemistry and genetics. Its interactions with the rest of the piRNA pathway will be probed as well as how the piRNAs will eventually be loaded into the Piwi protein PRG-1. Additionally, we will study homologs in mammalian cells, since the class of enzyme that we have identified has been only poorly studied thus far, and has been implicated in other important processes such as RNA quality control and viral replication.

For more information on the projects and requirements, please visit the respective Websites:
Project 1: https://www.imb.de/students-postdocs/international-phd-programme/apply-to-ipp/projects-offered/rene-ketting-pei

Project 2: https://www.imb.de/students-postdocs/international-phd-programme/apply-to-ipp/projects-offered/rene-ketting-rna

The Institute of Molecular Biology (IMB, www.imb.de) is a centre of basic research on the campus of Mainz University, Germany. Our research focuses on the biology of the nucleus, ranging from the molecular to the organismic level. We are currently recruiting new doctoral students as part of our winter call for the International PhD Programme (IPP).

If you are interested in this positions, please apply here. The deadline for applications is 19 November 2022. More information can be found on our website: https://www.imb.de/phd