SPP 2191:  Molecular Mechanisms of Functional Phase Separation

• Subject Area: Biology ; Chemistry ; Mathematics ; Medicine ; Physics
• Term: since 2019
• Website: Homepage
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 402723784

The evolution of complex eukaryotes went along with the need to compartmentalize and separate cellular processes, often in the form of membrane-encapsulated organelles like the nucleus, mitochondria, the endoplasmic reticulum, the Golgi apparatus, endosomes and lysosomes, which have the status of textbook knowledge. Membrane encapsulation was associated with the problem of developing some form of transport system such that biomolecules can exchange between organelles. Other long-known compartments are membraneless organelles, such as nucleoli, stress granules or Cajal bodies. However, only within the last decade it has become clear that these compartments arise from the physical process of phase separation, which bestows them with very special properties; they can be reversible, highly dynamic, and they continuously exchange molecules with their surroundings without the requirement of specific transport systems. These properties require us to rethink the organization of cells and to evolve our existing concepts of compartmentalization and regulation of cellular transport and functions, setting the stage for ‘cell biology 2.0’. To investigate these newly emerging concepts and elucidate the mechanisms that underlie cellular compartmentalization via phase separation and regulation thereof, we also need to develop new tools and approaches and combine cell biology and biophysics with biochemical reconstitution as well as theory and modelling. This combination of disciplines will allow us to make testable predictions about the role of phase separation in diverse biological processes, which will be validated in relevant functional biochemical assays as well as cell biological, developmental and disease models. The last ten years of phase separation research have only scratched the surface of the complexity of biomolecular condensates. The initial excitement about the role of phase separation has recently been extended to include more solid types of condensates which enable additional layers of functional regulation. This national priority program brings together scientists from diverse fields, thinking environments and scientific backgrounds. This network will allow researchers to synergistically decipher how novel functions, but also pathologies, emerge from the process of condensation, and what molecular underpinnings facilitate and regulate this key process. By doing so, this program will nourish a new generation of scientists who challenge the boundaries of existing fields and tackle important emerging problems in the life sciences through the lens of condensates.

• DFG Programme: Priority Programmes
• International Connection: United Kingdom

Projects

• Active microemulsification as a principle of chromatin organization and its role in cell fate induction (Applicants Hilbert, Ph.D., Lennart ;  Zaburdaev, Ph.D., Vasily )
• Condensation of ribosomal proteins in ribosome biogenesis and neurological ribosomopathy (Applicants Kraushar, Ph.D., Matthew ;  Nikolay, Rainer ;  Wegmann, Ph.D., Susanne )
• Conformational selection in liquid-liquid phase separation: Protein folding and aggregation pathways in the cytoplasm and stress granules (Applicant Ebbinghaus, Simon )
• Coordination Funds (Applicant Lemke, Edward A. )
• Development of a Combined Fluorescence, Optical Diffraction Tomography and Brillouin (FOB) Microscope for the Quantitative Investigation of Phase Transitions in Cells (Applicants Alberti, Simon ;  Guck, Jochen )
• Dissecting the nuclear pore-like permeability barrier function of phase separated liquid FG nucleoporin condensates (Applicants Lemke, Edward A. ;  Michels, Ph.D., Jasper ;  Parekh, Sapun )
• Dissecting the principles guiding CTCF condensate formation in cellular ageing (Applicant Papantonis, Argyris )
• Driving forces and pathological consequences of aberrant TDP-43 phase transitions in neurons and glial cells (Applicants Dormann, Dorothee ;  Ninkovic, Jovica )
• Dynamics and Buffering Functions of Nuclear Actin-Cofilin Assemblies in Cellular Stress Response (Applicant Mahamid, Ph.D., Julia )
• Mechanisms of biomolecular condensation in bacterial ribosomal RNA transcription (Applicants Duss, Ph.D., Olivier ;  Hennig, Janosch ;  Mahamid, Ph.D., Julia )
• Microfluidic analysis of multicomponent phase separation in ubiquitin-dependent proteostasis. (Applicant Heymann, Michael )
• Molecular and Cellular Determinants of Tau Protein Condensation into Dense Liquid Phases (Applicants Betzel, Christian ;  Mandelkow, Eckhard ;  Wegmann, Ph.D., Susanne )
• Molecular mechanisms and functional implications of Ded1p phase separation. (Applicant Sprangers, Remco )
• Molecular mechanisms and physiological functions of DNA damage condensates (Applicants Alberti, Simon ;  Seidel, Claus )
• Molecular mechanisms of condensate-membrane interaction and mutual reshaping (Applicants Agudo-Canalejo, Jaime ;  Knorr, Roland L. )
• Molecular mechanisms of functional liquid-liquid phase separation of Drosophila Loqs, Ago2 and dsRNA during siRNA biogenesis (Applicants Förstemann, Klaus ;  Sattler, Michael )
• Molecular mechanisms of functional phase separation in eukaryotic gene transcription (Applicants Cramer, Patrick ;  Söding, Johannes ;  Zweckstetter, Markus )
• Phase separation in PML nuclear bodies through a multivalent polySUMO-2/3 network is required for efficient DNA recombination and repair (Applicants Dittrich, Peter ;  Hemmerich, Peter )
• Phase separation of Ki-67 during mitotic exit (Applicant Cuylen-Häring, Sara )
• Phase separation of membrane scaffolding proteins as a mechanism to control formation of tight junctions (Applicants Honigmann, Alf ;  Weber, Christoph )
• Post-translational control of gene expression noise by liquid-liquid phase separation (Applicants Hyman, Anthony A. ;  Zechner, Christoph )
• Revealing the contribution of phase separation for establishing heterochromatin domains (Applicants Imhof, Axel ;  Rippe, Karsten )
• Role of sub-membranous phase separation in the regulation of myelin membrane structure and function (Applicant Simons, Mikael Jakob )
• Temperature-dependent phase separation of RNA binding proteins in chloroplasts (Applicants Sattler, Michael ;  Schmitz-Linneweber, Christian )
• The formation of phase-separated transcription hubs and their function in transcription regulation (Applicants Brugués, Ph.D., Jan ;  Vastenhouw, Nadine )
• The role of membrane protein phase separation in nuclear membrane sealing and fusion (Applicant von Appen, Alexander )

• Spokesperson: Professor Dr. Edward A. Lemke