Projects Offered

1 PhD project offered in the IPP winter call Molecular Mechanisms in Genome Stability & Gene Regulation

Scientific Background

Germ cells can be considered the most important cells of a species, as via these cells the genetic information is passed on to the offspring. Being the only cell type whose genome will be passed on between generations, these cells are the primary target of so-called genetic parasites, or transposons. These selfish pieces of DNA have as only goal to replicate within the genome and in doing so, they often cause mutations in the genome. It is thus not surprising that transposon activity has been responsible for major evolutionary events. However, excessive transposon activity kills a cell, because of genotoxic stress. As transposons are primarily active in the germ cells, these cells have evolved intricate transposon-defense systems. One of these is based on the activity of small non-coding RNAs. These are an important research-target in our laboratory.

Small non-coding RNAs are bound by Argonaute protein, that use these small RNAs as guides to identify target transcripts. These transcripts are then silenced by cleavage or through changes in chromatin that prevent their transcription. Curiously, many different small RNA pathways appear to act in parallel in germ cells. Notably in the germ cells of the nematode C. elegans this is very clear. The various small RNA pathways can have distinct and overlapping targets and can execute their activity in different ways. Understanding how these pathways work, how they can operate in parallel without becoming convoluted, how they select their targets and how they couple to other important RNA-based processes are questions that are currently prime research drivers in our and many other labs across the globe. 

One phenomenon that plays an important role in these processes is known as phase separation. This can lead to local enrichments of RNA and protein, creating so-called germ granules. These granules are considered to be like organelles, but then without a membrane. How these granules form and function is therefore also a major research area in our group. Interestingly, this particular research area links to neurological diseases in which inappropriate protein aggregation causes damage. Examples of such diseases are ALS, FTD but also forms of dementia. Understanding how germ granules work will hopefully also shed some light on how such diseases can be treated or prevents.

PhD Project: Controlling target specificity of small RNA pathways

Various lines of research are currently open to fresh input from new PhD students. What exactly the project will be will strongly depend also on your interests and skills. Here I sketch some rough indications in which the research is developing and to which you may be able to contribute.

First, we are looking at how the process of transcription termination couples to small RNA biogenesis. Several lines of evidence indicate that the mode of termination can be decisive about whether a transcript feeds into small RNA production or not. How this happens and what the consequences of these effects are, is currently completely unclear. We want to address this issue using genetics and genomics approaches. With genetics we will screen for factors that affect the link between termination and small RNAs. The genomics aspect will use various RNAseq approaches (short read and direct RNA sequencing) to better understand the genomic features of the loci affected by these effects.

Second, we are using extensive microscopy and biochemistry techniques to better understand the germ granules. What are their properties and how do they recruit specific proteins? Based on both in vivo and in vitro studies we are starting to understand some of the underlying principles of germ granule biology and future work is aimed at gaining much more detailed insights, to the extent that we can maybe design specific ger granules for a dedicated purpose. Here we collaborate closely with the Stelzl Lab, who bring physics into this project, making it a very interdisciplinary research area.

In both these research lines we make extensive use of genome editing using CrisprCas, protein purification, microscopy, genetics and bioinformatics. In collaboration with the Falk lab from the Max Perutz Labs in Vienna, and with Ulrich Hohmann, Katka Luck and Laura Lorenzo-Orts from the IMB we also increasing use structure determination and predictions in our work. 

Everything considered, the work in this project will be challenging and exciting, and it will ask for flexibility and dedication to bring to a successful end. In return, our lab offers a stimulating environment, with ample opportunities also for social interactions and activities. We are looking forward to your application!

If you are interested in this project, please select Ketting as your group preference in the IPP application platform.

Publications relevant to this project

Pereirinha J, Brehm M, Govind S, Busch A, Podvalnaya N, Seistrup AS, Delaney K, Steiner F, Konig J, Falk S, Ketting RF (2026) SLBP-independent control of maternal histone mRNA. BioRxiv Link 

Govind S, Ruppert S, Kirangwa J, Busetto V, Nischwitz E, Almeida M, Hellmann S, Witte H, Sommer RJ, Butter F, Falk S, Sarkies P, Ketting RF (2025) An Evolutionarily Conserved N-terminal Domain of RRF-3 Governs GTSF-1 Binding in Nematodes. EMBO Rep.in press

Isolehto I, Pshanichnaya L, Páez-Moscoso DJ, Mager M, Seistrup AS, Schreier J, Hellmann S, Gaurav K, Kielisch F, Chen J, Stelzl LS, Ketting RF (2025) Proteolytic Control of an Auto-inhibitory Intrinsically Disordered Region Governs Small RNA Selectivity in Argonaute Proteins. BioRxiv Link

Seistrup AS, Nischwitz E, Butter F, Ketting RF (2026) Crosstalk between and developmental dynamics of C. elegans Argonaute proteins. Genetics May 6;233(1):iyag077. Link

Schreier J, Pshanichnaya L, Kielisch F, Ketting RF (2025) A genetic framework for RNAi inheritance in Caenorhabditis elegans. EMBO Rep. 26, 4072–4099. Link

Podvalnaya N, Bronkhorst AW, Lichtenberger R, Hellmann S, Nischwitz E, Falk T, Karaulanov E, Butter F, Falk S, Ketting RF (2023) piRNA processing by a trimeric Schlafen-domain nuclease. Nature 622, 402–409. Link

Schreier J, Dietz S, Boermel M, Oorschot V, Seistrup AS, de Jesus Domingues AM, Bronkhorst AW, Nguyen DAH, Phillis S, Gleason EJ, L'Hernault SW, Phillips CM, Butter F, Ketting RF (2022) Membrane-associated cytoplasmic granules carrying the Argonaute protein WAGO-3 enable paternal epigenetic inheritance in Caenorhabditis elegans. Nat. Cell Biol. 24, 217–229. Link

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