Molecular Mechanisms in Epigenetic Inheritance - PEI granules

1 PhD project offered in the IPP winter call 2022

Scientific Background

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: 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.

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

Publications relevant to this project

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 elegansNat. Cell Biol. 24: 217–229

Perez-Borrajero C, Podvalnaya N, Holleis K, Lichtenberger R, Karaulanov E, Simon B, Basquin J, Hennig J*, Ketting RF*, Falk S*. (2021) Structural basis of PETISCO complex assembly during piRNA biogenesis in C. elegans. Genes Dev. 35(17-18):1304-1323.
*: shared corresponding authorship

Ketting RF*, Cochella L*. (2021) Concepts and functions of small RNA pathways in C. elegans. Curr. Top. Dev. Biol. 144:45-89
*: shared corresponding authorship

Placentino MP, de Jesus Domingues AM, Schreier J, Dietz S, Hellmann S, de Albuquerque BF, Butter F, Ketting RF. (2021) Intrinsically disordered protein PID-2 modulates Z granules and is required for heritable piRNA-induced silencing in the Caenorhabditis elegans embryo.  EMBO J. 40(3):e105280

Rodrigues RJC, de Jesus Domingues AM, Hellmann S, Dietz S, de Albuquerque,BFM, Renz C, Ulrich HD, Sarkies P, Butter F, Ketting RF. (2019) PETISCO is a novel protein complex required for 21U RNA biogenesis and embryonic viability Genes Dev 33(13-14):857-870.

Roovers EF, Kaaij LJT, Redl S, Bronkhorst AW, Wiebrands K, de Jesus Domingues AM, Huang HY, Han CT, Riemer S, Dosch R, Salvenmoser W, Grün D, Butter F, van Oudenaarden A, Ketting RF. (2018) Tdrd6a Regulates the Aggregation of Buc into Functional Subcellular Compartments that Drive Germ Cell Specification. Dev Cell. 46(3):285-301.

de Albuquerque BF, Placentino M, Ketting RF. (2015) Maternal piRNAs Are Essential for Germline Development following De Novo Establishment of Endo-siRNAs in Caenorhabditis elegansDev Cell. 34(4):448-56.

de Albuquerque BFM, Luteijn MJ, Cordeiro Rodrigues RJ, van Bergeijk P, Waaijers S, Kaaij LJT, Klein H, Boxem M and Ketting RF (2014) PID-1 is a novel factor that operates during 21U-RNA biogenesis in Caenorhabditis elegans. Genes Dev. 28(7):683-8

van Wolfswinkel JC, Claycomb JM, Batista PJ, Mello CC, Berezikov E, Ketting RF (2009) CDE-1 affects chromosome segregation through uridylation of CSR-1-bound siRNAs. Cell 139(1):135-148

Houwing S, Kamminga LM, Berezikov E, Cronembold D, Girard A, van den Elst H, Filippov DV, Blaser H, Raz E, Moens CB, Plasterk RH, Hannon GJ, Draper BW, Ketting RF (2007) A role for Piwi and piRNAs in germ cell maintenance and transposon silencing in Zebrafish. Cell 129(1):69-82


Prof. Dr René Ketting