Mechanisms of Epigenetic Inheritance

• Applicant: Professor René Ketting, Ph.D.
• Subject Area: General Genetics and Functional Genome Biology ; Cell Biology
• Term: from 2014 to 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 252386272

• Final Report Year: 2024

Final Report Abstract

The inheritance of genetic information across cell divisions is key to life. However, in many cases, not only the DNA needs to be inherited, but also the instructions of how to use the DNA. This layer of so-called epi-genetic information provides context to all the possible products that can be generated from the DNA and ensures that only the correct and required products are made at any particular time. During sexual reproduction, much of the epigenetic information typically is removed, as the germ cells need to be able to trigger the formation of a new embryo, in which gene-regulatory networks can be built up from scratch. Nevertheless, some epigenetic information can be inherited during sexual reproduction. It is thought that such inheritance can help prime the offspring to adept to specific environmental conditions, but a major role may also be to help the offspring identify endogenous parasites, such as transposons, that are hiding in its genome. One mechanism that can mediate such transgenerational epigenetic inheritance rests on the activity of small RNA molecules, that can silence gene expression and transposable element activity. Small RNAs always do this while being bound to so-called Argonaute proteins. In this project we have studied molecular mechanisms that make such small RNA mediated inheritance possible. First, we identified a novel enzyme that helps generate these small RNAs. Second, we have studied how Argonaute proteins are modified by proteases, such that they can work properly. Third, we have studied how post-translational modification by a kinase may help organize the subcellular organization of small RNA machinery within the cytoplasm of the germ cells. With these results in hand, we are now in a better position to further unravel the very complex mechanisms that are driving epigenetic inheritance through small RNAs.

Publications

• piRNA processing by a trimeric Schlafen-domain nuclease. Nature, 622(7982), 402-409.
  Podvalnaya, Nadezda; Bronkhorst, Alfred W.; Lichtenberger, Raffael; Hellmann, Svenja; Nischwitz, Emily; Falk, Torben; Karaulanov, Emil; Butter, Falk; Falk, Sebastian & Ketting, René F.
  
• MUT-7 exoribonuclease activity and localization are mediated by an ancient domain. Nucleic Acids Research, 52(15), 9076-9091.
  Busetto, Virginia; Pshanichnaya, Lizaveta; Lichtenberger, Raffael; Hann, Stephan; Ketting, René F. & Falk, Sebastian
  
• Regulation of Microprocessor assembly and localization via Pasha’s WW domain in C. elegans. openRxiv.
  Montgomery, Brooke E.; Knittel, Thiago L.; Reed, Kailee J.; Chong, Madeleine C.; Isolehto, Ida J.; Cafferty, Erin R.; Smith, Margaret J.; Sprister, Reese A.; Magelky, Colin N.; Scherman, Hataichanok; Ketting, Rene F. & Montgomery, Taiowa A.
  
• A genetic framework for RNAi inheritance in Caenorhabditis elegans. EMBO Reports, 26(16), 4072-4099.
  Schreier, Jan; Pshanichnaya, Lizaveta; Kielisch, Fridolin & Ketting, René F.