ERC FUNDED PROJECTS

Branching morphogenesis, the process by which branched organs such as the lung, prostate, kidney or mammary gland are generated, is a paradigmatic example of complex developmental processes bridging multiple scales. The mechanisms through which given molecular signals and cellular behaviours give rise to a robust organ structure remains a fundamental and open question, for which theoretical methods are needed. Our experience in modelling cytoskeletal mechanics, stem cell dynamics and branching processes puts us in a unique position to tackle this fascinating problem, by combining systems biology and biophysical approaches at multiple scales. In particular, we will focus on: 1. Understanding how stochastic rules lead to robust morphogenetic outputs at the organ scale, and which constraints and optimal design principles they impose on physiological function. 2. Characterizing at the cellular scale the bi-directional feedbacks coordinating fate choices of stem/progenitor cells and niche signals during the extensive remodelling events that branching morphogenesis entails. 3. Developing at the subcellular and cellular scale an integrated mechanochemical theory of pattern formation in branched organs, to understand the coordination of mechanical forces and chemical signals defining their global structure. Towards these goals, we will combine analytical and numerical tools with data analysis methods, to reach a quantitative understanding of the emergent mechanisms driving branching morphogenesis. We will challenge our theoretical predictions with published datasets available for different organs, as well as design specific experimental tests in collaboration with experimental biology groups. This will allow us to compare and contrast different systems, and extract generic classes of design principles of organogenesis across length scales. With this, we expect to generate novel insights of broad relevance for the fields of systems, computational and developmental biology.

1 452 604 €

Start date: 2020-07-01, End date: 2025-06-30

"Our existence as human beings is based on plants and their products. Worldwide, crops are threatened by pests including biotrophic fungi. Therefore, it is of vital interest to develop new strategies to reduce crop losses and to improve crop plants for the growing world population. Biotrophic plant pathogens employ small secreted molecules, so-called effectors, to overcome plant defence systems and to establish biotrophy. The rapid increase in available genome sequences of biotrophic pathogens and in transcriptomic datasets of their biotrophic stages allow us to identify putative secreted proteinaceous effectors by bioinformatic means. However, our insight into the functions of these effectors is still very limited. In this proposal, the PI´s extensive experience on both the plant host side and the fungal pathogen side of the biotrophic interaction is exploited to develop a workflow for functional, partially robotic-based screens to fill this gap. The combination of screen-deduced functional information with the analysis of effector localisation and specific host interactors will provide the basis for formulating starting hypotheses of effector function. These will then be tested in individual case studies, employing the well established Ustilago maydis-Zea mays as well as the new Ustilago bromivora-Brachypodium distachyon model systems. The project will be conducted at the Max Planck Institute (MPI) for Terrestrial Microbiology in a highly stimulating scientific environment. Linking the dramatic morphological changes and underlying molecular events during biotrophy on the host side to the action of subsets or even single effector proteins will allow the creation of a synthetic effectome. The deep functional understanding of the manipulative toolbox of biotrophs has the potential to facilitate transgenic crop development and will open a new era in the development of sustainable antifungal plant protection strategies."

1 446 316 €

Start date: 2014-02-01, End date: 2019-01-31

A major goal in biology is to understand how gene regulatory information is encoded by the human genome and how it defines different gene expression programs and cell types. Enhancers are genomic elements that control transcription, yet despite their importance, only a minority of enhancers are known and functionally characterized. In particular, their activity changes during cellular signalling or cell type transitions are largely elusive. Furthermore, fundamental questions about transcriptional co-factors have remained unanswered even though they regulate enhancer activities and have become attractive therapeutic targets, e.g. for cancer treatment. Here, I propose a functional genomics approach in mammalian cells with three specific objectives: First, we will identify and functionally characterize transcriptional enhancers in selected human and mouse cells using the recently developed quantitative enhancer activity assay STARR-seq. Second, we will determine enhancer activity changes quantitatively during steroid hormone signalling, cell differentiation, and malignant transformation to reveal enhancers that are important for these processes. Third, we will systematically dissect the functional relationship of enhancers and transcriptional co-factors. This proposal uses emerging in-house technology to address fundamental questions in enhancer biology and complement the genome-wide profiling of gene expression and chromatin states (e.g. by ENCODE). We will gain insights into the genomic organization of active enhancers and reveal chromatin or sequence features associated with dynamic activity changes. I also expect that we will be able to define co-factor requirements for enhancer function and reveal if different types of enhancers exist. Given our expertise in experimental and computational approaches and STARR-seq, I anticipate that we reach our aims and make major contributions to the understanding of gene regulation in mammals.

1 999 906 €

Start date: 2015-09-01, End date: 2021-07-31

Chemical exchange between cells and their environment occurs at cellular membranes, the interface where biology meets chemistry. Studying mechanisms of drug resistance, I realized that SoLute Carrier proteins (SLCs), not only represent the major class of small molecule transporters, but that they are encoded by one of the most neglected group of human genes. I identified a case where an SLC controls the activity of mTOR, suggesting that other SLCs may be involved in signalling. This formed the basis for the GameofGates project proposal. The name refers to SLCs as a metaphor for cellular gates coordinating access to resources following game rules that are largely unknown but worth learning, as the acquired knowledge could impact our understanding of cellular physiology and open avenues for innovative treatment of human diseases. GameofGates (GoG) plans the investigation of SLC function by comprehensively and deeply charting the genetic and protein interaction landscape of SLCs in a human cell line, while monitoring fitness, drug sensitivity and metabolic state. GoG aims at functionally de-orphanize many SLCs by assessing hundreds of thousands of genetic interactions as well as thousands protein and drug interactions. I hypothesize that SLC action is linked to signalling pathways and plays an important role in integration of metabolism and cell regulation for successful homeostasis. I propose that whole circuits of SLCs may be linked to particular nutrient auxotrophy states and that knowledge of these dependencies could instruct assessment of vulnerabilities in cancer cells. In turn, these could be pharmacologically exploited using existing or future drugs. Overall, GoG should position enough pieces into functional and regulatory networks in the SLC puzzle game to facilitate future work and motivate the community to embrace investigation of SLCs as conveyers of metabolic and chemical integration of cell biology with physiology and, in a wider scope, ecology.

2 389 782 €

Start date: 2016-10-01, End date: 2021-09-30