PhD positions in small RNA biology (f/m/x)
The Förstemann lab at the Gene Center of the Ludwig-Maximilians University Munich (LMU) has a job opening:
PhD positions in small RNA biology (f/m/x)
Small RNAs participate in many aspects of transcriptional and post-transcriptional regulation events. This also includes aspects of genome maintenance, in particular the control of horizontally transferred genetic elements (transposons, viruses). We use the fruit fly Drosophila melanogaster as a model organism to study how small RNAs are specifically generated, how the self vs. non-self distinction can be made in the genome and which biochemical phenomena contribute to the efficiency and specificity of small RNA biogenesis and function. With our model system, we have access to cell extracts + in vitro biochemistry, cell culture systems but also in vivo assays using mutant / transgenic / genome-edited flies.
You will use cutting-edge tools in the areas of functional genomics, synthetic biology, biochemistry and cellular biology to unlock the inner workings of mitochondrial stress signaling in the human system. This includes genome-wide forward genetic screening based on flow cytometry, precision CRISPR genome engineering, in-organello experimentation, and the development of new cell-based assays no one is thinking of today. Your goal will be to uncover novel pathways and genetic networks that protect the cell's most precious organelle (mitochondria) from harm and decipher their molecular modes of operation. Your project will be highly interdisciplinary and offer ample opportunities for collaborations with world-leading experts in different areas of biology.
In our efforts to study the self vs. non-self distinction in the genome, we discovered that siRNAs are generated at DNA double-strand breaks, provided they occur in a region that is actively transcribed (Michalik et al. 2012). This appears to be connected to the spliceosome (Merk et al. 2017) and is due to RNA polymerase II initiating a transcript at the break (Bottcher et al. 2022). We now want to “build a molecular bridge” between the spliceosome and the antisense-running RNA polymerase. Our genome-wide screen has produced candidates for that (Merk et al. 2017), which we are following up with biochemical and genetic approaches (including deep sequencing of small RNAs + data analysis).
The small RNAs that are involved in genome maintenance have specific requirements during their biogenesis. We discovered a particular splice variant of the dsRNA binding protein Loquacious (Loqs) that is required (Hartig et al. 2009) and constitutes an alternative version of an siRNA loading complex (Hartig et al. 2011, Tants et al. 2017). Our unpublished work has shown that the protein participates in a phase-separation phenomenon in living cells. We will use biochemical assays (e.g. proximity-based biotinylation), fluorescence microscopy and cell culture or transgenic flies to determine the composition of these condensates and the molecular consequences of their formation in vivo. Again, deep sequencing of small RNAs + data analysis will be an important tool to describe the molecular phenotype.
I am looking forward to your application! Please introduce yourself briefly, join a CV and the contact information for two academic references in an email to firstname.lastname@example.org. The University of Munich is an equal opportunity employer. Handicapped candidates with equal qualifications will be given preference, a part-time employment is in principle possible.
Bottcher, R., et al. (2022). "RNA polymerase II is recruited to DNA double-strand breaks for dilncRNA transcription in Drosophila." RNA Biol 19(1): 68.
Hartig, J. V., et al. (2009). "Endo-siRNAs depend on a new isoform of loquacious and target artificially introduced, high-copy sequences." Embo J 28(19): 2932.
Hartig, J. V., et al. (2011). "Loqs-PD and R2D2 define independent pathways for RISC generation in Drosophila." Nucleic Acids Res 39(9): 3836.
Merk, K., et al. (2017). "Splicing stimulates siRNA formation at Drosophila DNA double-strand breaks." PLoS Genet 13(6): e1006861.
Michalik, K. M., et al. (2012). "A small RNA response at DNA ends in Drosophila." Nucleic Acids Res 40(19): 9596.
Tants, J. N., et al. (2017). "Molecular basis for asymmetry sensing of siRNAs by the Drosophila Loqs-PD/Dcr-2 complex in RNA interference." Nucleic Acids Res 45(21): 12536.
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