ERC FUNDED PROJECTS

The human genome carries genetic information in two distinct forms: Transcribed genes and regulatory DNA elements (rDEs). rDEs control the magnitude and pattern of gene expression, and are indispensable for organismal development and cellular homeostasis. Nevertheless, while large-scale functional genetic screens greatly advanced our knowledge in studying mammalian genes, such tools to study rDEs were lacking, impeding scientific progress. Interestingly, recent advance in genome editing technologies has not only expanded the available screening toolbox to examine genes, but also opened up novel opportunities in studying rDEs. We distinguish two types of rDEs: Transcriptional rDEs that recruit transcription factors to enhancers, and structural rDEs that maintain chromatin 3D structure to insulate transcriptional activities, a feature postulated to be essential for gene expression regulation by enhancers. Recently, we developed a CRISPR strategy to target enhancers. We showed its scalability and effectivity in identifying potential oncogenic and tumour-suppressive enhancers. Here, we will exploit this line of research and develop novel strategies to target structural rDEs (e.g. insulators). By setting up functional genetic screens, we will identify key players in cell proliferation, differentiation, and survival, which are related to cancer development, metastasis induction, and acquired therapy resistance. We will validate key insulators and decipher underlying mechanisms of action that control phenotypes. In a parallel approach, we will analyse whole genome sequencing datasets of cancer to identify and characterize genetic aberrations occurring in the identified regions. Altogether, the outlined research plan forms a natural extension of our successful functional approaches to study gene regulation. Our results will setup the foundation to better understand principles of chromatin architecture in gene expression regulation in development and cancer.

2 497 000 €

Start date: 2019-09-01, End date: 2024-08-31

Feeding the growing world population under changing climate conditions poses an unprecedented challenge on global agriculture and our current pace to breed new high yielding crop varieties is too low to face the imminent threats on food security. This ERC project proposes a novel crossing scheme that allows for an expeditious evaluation of combinations of potential yield contributing alleles by unifying ‘classical’ breeding with gene-centric molecular biology. The acronym BREEDIT, a word fusion of breeding and editing, reflects the basic concept of combining breeding with multiplex genome editing of yield related genes. By introducing plants with distinct combinations of genome edited mutations in more than 80 known yield related genes into a crossing scheme, the combinatorial effect of these mutations on plant growth and yield will be evaluated. Subsequent rounds of crossings will increase the number of stacked gene-edits per plant, thus increasing the combinatorial complexity. Phenotypic evaluations throughout plant development will be done on our in-house automated image-analysis based phenotyping platform. The nature and frequency of Cas9-mediated mutations in the entire plant collection will be characterised by multiplex amplicon sequencing to follow the efficiency of CRISPR-cas9 genome editing and to identify the underlying combinations of genes that cause beneficial phenotypes (genetic gain). The obtained knowledge on yield regulatory networks can be directly implemented into current molecular breeding programs and the project will provide the basis to develop targeted breeding schemes implementing the optimal combinations of beneficial alleles into elite material. BREEDIT will be a major step forward in integrating basic knowledge on genes with plant breeding and has the potential to provoke a paradigm shift in improving crop yield.

2 474 790 €

Start date: 2019-09-01, End date: 2025-02-28

Deciphering and engineering the assembly of cellular organelles is a key pursuit in biology. The centriole is an evolutionarily conserved organelle well suited for this goal, and which is crucial for cell signaling, motility and division. The centriole exhibits a striking 9-fold radial symmetry of microtubules around a likewise symmetrical cartwheel containing stacked ring-bearing structures. Components essential for generating this remarkable architecture from alga to man have been identified. A next critical step is to engineer assays to probe the dynamics of centriole assembly with molecular precision to fully understand how these components together build a functional organelle. Our ambitious research proposal aims at taking groundbreaking steps in this direction through four specific aims: 1) Reconstituting cartwheel ring assembly dynamics. We will use high-speed AFM (HS-AFM) to dissect the biophysics of SAS-6 ring polymer dynamics at the root of cartwheel assembly. We will also use HS-AFM to analyze monobodies against SAS-6, as well as engineer surfaces and DNA origamis to further dissect ring assembly. 2) Deciphering ring stacking mechanisms. We will use cryo-ET to identify SAS-6 features that direct stacking of ring structures and set cartwheel height. Moreover, we will develop an HS-AFM stacking assay and a reconstituted stacking assay from human cells. 3) Understanding peripheral element contributions to centriole biogenesis. We will dissect the function of the peripheral centriole pinhead protein Cep135/Bld10p, as well as identify and likewise dissect peripheral A-C linker proteins. Furthermore, we will further engineer the HS-AFM assay to include such peripheral components. 4) Dissecting de novo centriole assembly mechanisms. We will dissect de novo centriole formation in human cells and water fern. We will also explore whether de novo formation involves a phase separation mechanism and repurpose the HS-AFM assay to probe de novo organelle biogenes

2 500 000 €

Start date: 2019-09-01, End date: 2024-08-31

This project is devoted to the mathematical analysis of important physical properties of many-body quantum systems. We will be interested in properties of the ground state and low-energy excitations but also of non-equilibrium dynamics. We are going to consider systems with different statistics and in different regimes. The questions we are going to address have a common aspect: correlations among particles play a crucial role. Our main goal consists in developing new tools that allow us to correctly describe many-body correlations and to understand their effects. The starting point of our proposal are ideas and techniques that have been introduced in a series of papers establishing the validity of Bogoliubov theory for Bose gases in the Gross-Pitaevskii regime, and in a recent preprint showing how (bosonic) Bogoliubov theory can also be used to study the correlation energy of Fermi gases. In this project, we plan to develop these techniques further and to apply them to new contexts. We believe they have the potential to approach some fundamental open problem in mathematical physics. Among our most ambitious objectives, we include the proof of the Lee-Huang-Yang formula for the energy of dilute Bose gases and of the corresponding Huang-Yang formula for dilute Fermi gases, as well as the derivation of the Gell-Mann--Brueckner expression for the correlation energy of a high density Fermi system. Furthermore, we propose to work on long-term projects (going beyond the duration of the grant) aiming at a rigorous justification of the quantum Boltzmann equation for fermions in the weak coupling limit and at a proof of Bose-Einstein condensation in the thermodynamic limit, two very challenging and important questions in the field.

1 876 050 €

Start date: 2019-09-01, End date: 2024-08-31