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We investigate the co-evolution of eukaryotic genomes with transposons, a diverse class of mobile and selfish elements. This ancient genetic conflict has major impacts on gene regulatory networks, chromatin & chromosome architecture, as well as gametogenesis and speciation. It is also interesting to note that some of the most transformative molecular tools such as restriction endonucleases, RNA interference, and CRISPR/Cas emerged from the broad domain of genome defense. Our approach is to study this arms race from the angle of host defense mechanisms that restrict transposon activity and protect the genome against ectopic recombination. We focus on the piRNA pathway, which acts as a small RNA-based genome immune system in animal gonads to safeguard genome integrity and fertility.
The enormous precision of gene expression during multicellular development all too easily gives the impression of a ‘harmonic genome’, where coding sequences and regulatory elements are arranged in highly evolved ways. Eukaryotic genomes, however, are anything but harmonic. They are loaded with transposable elements and their sequence remnants. Half of the human genome has a recognizable transposon origin. Even more extreme are some amphibians and flowering plants, whose genomes have staggeringly high transposon contents of ~90%. How do cells cope with this massive and repetitive sequence load? How do they restrict transposon activity while leaving their own gene expression programs unperturbed? Do genomes take advantage of this repetitive sequence reservoir for their own purposes? And if so, how?
We are fascinated by the above questions, and we approach them by studying a recently discovered genome surveillance system in animals, the gonad specific PIWI/piRNA pathway. This RNA interference pathway acts like a small RNA-mediated genome immune system: it selectively silences transposons, it establishes heterochromatin at repeats, and it quickly adapts to new genome invaders. Over the last few years, research in the piRNA field has led to the discovery of several processes and biochemical activities that were not even considered to exist. Who would have imagined a small RNA biogenesis platform on the outer mitochondrial membrane? Or non-canonical transcription within heterochromatin, through molecular hacking of the core gene expression machinery? It is this frequent venturing into the ‘unknown unknowns’ that we find particularly exciting.
Our aim is to provide molecular explanations for the biological processes that underlie or are controlled by the piRNA pathway. Genetic screens have unearthed a surprisingly high number (~40-50) of proteins with integral roles in this genome defense pathway, and we have assigned these proteins to specific processes. With this knowledge, we select key factors as entry points into understanding the conceptual architecture of this silencing system. Besides our strong background in genetics and genomics, we are increasingly excited about applying mechanistic and structural approaches to understand the molecular activities of the involved factors. Finally, the intersection of the piRNA pathway with germline biology has always been a source of fascination for us. For example, piRNAs are maternally inherited across generations and they act as true epigenetic vectors for silencing information. You can find more details on our main project areas here.
We strongly believe that progress in the piRNA field relies on developing new methods and applying diverse techniques from other fields to answer our questions. Our projects are therefore multidisciplinary in nature and involve genetics, genomics, biochemistry, imaging technologies, and computational biology. Most of us work with Drosophila melanogaster, the model system at the forefront of piRNA research. But being genetics aficionados, we are also venturing into transposon biology in mammalian systems, where recent advances in genetic tools have been truly transformative. We are supported by a diverse array of world class scientific facilities at the Vienna Biocenter ranging from mass spectrometry, biooptics, deep sequencing, recombinant protein production, Drosophila genome engineering and transgenics, and others.
Recorded live on June 15th at Carnegie Embryology in Baltimore, at the Carnegie Embryology Minisymposium 2018 on Molecular Mechanics of Adaptation. Julius Brennecke speaks about molecular and conceptual principles underlying the piRNA pathway, a small RNA guided defense pathway that protects the animal germline genome against mobile genetic elements.
Mostafa ElMaghraby, Vienna BioCenter PhD Student in the Brennecke Lab and DOC fellow of the Austrian Academy of Sciences explains how the cell rewires nuclear RNA export to protect genome integrity. In a collaboration with postdoc Peter Andersen (now faculty at Aarhus University, Denmark), Mostafa showed that the piRNA pathway utilizes and re-purposes preexisting building blocks in the cell to export the long single-stranded piRNA precursors from the nucleus and to target them to the cytoplasmic piRNA biogenesis machinery. Original publication: ElMaghraby, Andersen et al., "A heterochromatin-specific RNA export pathway facilitates piRNA production", Cell, DOI 10.1016/j.cell.2019.07.007
Mohn, F., Handler, D., Brennecke, J. (2015). Noncoding RNA. piRNA-guided slicing specifies transcripts for Zucchini-dependent, phased piRNA biogenesis. Science. 348(6236):812-817
Mohn, F., Sienski, G., Handler, D., Brennecke, J. (2014). The rhino-deadlock-cutoff complex licenses noncanonical transcription of dual-strand piRNA clusters in Drosophila. Cell. 157(6):1364-1379
Handler, D., Meixner, K., Pizka, M., Lauss, K., Schmied, C., Gruber, FS., Brennecke, J. (2013). The genetic makeup of the Drosophila piRNA pathway. Mol Cell. 50(5):762-77
Sienski, G., Dönertas, D., Brennecke, J. (2012). Transcriptional silencing of transposons by Piwi and maelstrom and its impact on chromatin state and gene expression. Cell. 151(5):964-80
Brennecke, J., Malone, CD., Aravin, AA., Sachidanandam, R., Stark, A., Hannon, GJ. (2008). An epigenetic role for maternally inherited piRNAs in transposon silencing. Science. 322(5906):1387-92
Brennecke, J., Aravin, AA., Stark, A., Dus, M., Kellis, M., Sachidanandam, R., Hannon, GJ. (2007). Discrete small RNA-generating loci as master regulators of transposon activity in Drosophila. Cell. 128(6):1089-103
- ERC Starting Grant (2010-2015)
- ERC Consolidator Grant (2016-2021)
- FWF SFB Grant “RNA Biology”
- FWF Doctoral Program “RNA Biology”
- Austrian Academy of Sciences