Molecular principles of the regulation of gene expression by liquid-liquid phase separation

1 PhD project offered in the IPP winter call 2020/2021

Scientific Background

Our aim is to understand how biomolecular condensates formed by liquid-liquid phase separation regulate gene expression using molecular simulations. Biomolecular condensates are phase-separated clusters of disordered proteins and nucleic acids. Post-transcriptional regulation of gene expression by biomolecular condensates, as revealed by Ketting and co-workers, is critical in the development of germ cells, which go on to develop to eggs and sperm. In general, little is known about how regulation in the context of biomolecular condensates happens on the molecular level. With advances in computer simulations we can use them as computational microscope to resolve molecular mechanisms, discover new biological connections by, e.g., identifying new interaction partners, and to guide experiments.

PhD Project: Post-transcriptional regulation by liquid-phase separation in developmental biology

In your research, you will investigate how liquid-liquid phase separation plays a regulatory role in germ cells and balances their RNA content. The interaction of the disordered protein Buc and multi Tudor domain protein Tdrd6a has been characterized in zebrafish, which revealed its importance for the assembly of condensates via liquid-liquid phase separation in the development of germ cells. The condensates bind mRNAs as messenger ribonucleoproteins (RNPs), which are critical for germ cell development, and these mRNPs self-associate during the assembly of the condensates. With multi-scale simulations you will elucidate at the molecular scale how Buc and Tdrd6a interact and improve our understanding of how their phase behaviour shapes germ cell development. You will investigate how mRNPs of the same kind self-associate and with simulations you will have a unique vantage point to investigate the driving hypothesis that the degree of self-interactions of mRNPs balances the mRNA content in condensates and germ cells.

You will join a young, dynamic and highly interdisciplinary research group. You will learn how to develop novel simulation approaches and apply them to important biological questions. As part of your computational research you will collaborate closely with the laboratory of Prof. René Ketting at IMB, which provides a unique opportunity to validate your findings experimentally.

We are looking for a highly motivated candidate with a strong interest in research at the interface of cell biology, computational biology and biophysics. Experience in computational biology, programming, molecular simulations or statistics are an advantage, but not required.

Publications relevant to this project

*Pietrek LM, *Stelzl LS, Hummer, G. (2020) Hierarchical Ensembles of Intrinsically Disordered Proteins at Atomic Resolution in Molecular Dynamics Simulations. J Chem Theory Comput, 16(1):725–737. *equal contributions

Benayad Z, von Bülow S, Stelzl LS, Hummer G (2020) Simulation of FUS Protein Condensates with an Adapted Coarse-Grained Model. bioRxiv. doi.org/10.1101/2020.10.10.334441.

Stelzl LS, Kells A, Rosta E, Hummer, G (2017) Dynamic Histogram Analysis To Determine Free Energies and Rates from Biased Simulations. J Chem Theory Comput, 13(12):6328–6342.

Roovers EF, Kaaij LJT, Redl S, Bronkhorst AW, Wiebrands K, de Jesus Domingues AM, Huang HY, Han CT, Riemer S, Dosch R, et al. (2018) Tdrd6a Regulates the Aggregation of Buc into Functional Subcellular Compartments That Drive Germ Cell Specification. Dev Cell, 46(3):285-301.e9. doi.org/10.1016/j.devcel.2018.07.009.

Stelzl LS, Mavridou DA, Saridakis E, Gonzalez D, Baldwin AJ, Ferguson SJ, Sansom MS, Redfield C (2020) Local Frustration Determines Loop Opening during the Catalytic Cycle of an Oxidoreductase. Elife, 9:e5466. doi.org/10.7554/eLife.54661.

 

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Dr Lukas Stelzl

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